Interferon alpha and beta Discovery and structure Type I interferons (IFN-I) comprise a wide class of structurally related cytokines, mostly recognized by their pivotal role in antiviral responses. 1 The most extensively studied members of IFN-I are interferon-α (IFN-α) and interferon-β (IFN-β). IFN-I regulate lymphocyte development, immune responses and the maintenance of immunological memory of cytotoxic T cells. In addition, they have a protective role in various pathophysiologic processes, but also detrimental effects on several autoimmune diseases. 2 At the end of 1950s interferon (IFN) was first described as a substance inducing the antiviral state in cells. 3 Later, interferons were grouped as type I IFNs (acid-stable at pH 2 and heat-stable) and type II IFNs, which are acid-labile, but so far there is only one member in this group – IFN-. (Reviewed in 4 ). More recently, type III IFNs were described, IFNs-ʎ (lambda). Type I IFNs are structurally related proteins that act on a common cell-surface IFN-α receptor (IFNAR). Members of this family include: IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin). All human type I IFN genes are clustered in the same locus on the short arm of chromosome 9. Homology between human IFN-and IFN-is about 30% and 45% at the amino acid and nucleotide level, respectively. IFN-, and (IFN-αβ) genes lack introns; this feature allows a more rapid transcription which is
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Interferon alpha and betaDiscovery and structureType I interferons (IFN-I) comprise a wide class of structurally related cytokines,
mostly recognized by their pivotal role in antiviral responses.1 The most extensively
studied members of IFN-I are interferon-α (IFN-α) and interferon-β (IFN-β). IFN-I
regulate lymphocyte development, immune responses and the maintenance of
immunological memory of cytotoxic T cells. In addition, they have a protective role in
various pathophysiologic processes, but also detrimental effects on several
autoimmune diseases. 2
At the end of 1950s interferon (IFN) was first described as a substance inducing
the antiviral state in cells. 3 Later, interferons were grouped as type I IFNs (acid-
stable at pH 2 and heat-stable) and type II IFNs, which are acid-labile, but so far
there is only one member in this group – IFN-. (Reviewed in 4). More recently, type
III IFNs were described, IFNs-ʎ (lambda).
Type I IFNs are structurally related proteins that act on a common cell-surface
IFN-α receptor (IFNAR). Members of this family include: IFN-α (alpha), IFN-β (beta),
Roferon-A (Recombinant IFN-α-2a), Intron A (Recombinant IFN--α-2b), PEG Intron
(PEG recombinant IFN--α-2b) and Avonex (IFN-β-1a). Additionally, they are tested in
clinical trials for safety and potential treatment of lymphomas60 and hepatocellular
carcinoma, 61, 62
Role in allergic diseaseThe importance of IFN-αβ-mediated suppression of allergic T cell subsets is
underscored by studies demonstrating that pDCs from asthmatic patients secrete
less IFN-αβ than healthy donor pDCs in response to viral infections and toll-like
receptor (TLR) ligands.63, 64 Similarly, impaired IFN-β levels, in response to rhinovirus
infection, were found in epithelial cells from asthmatic children. 65 The cause of this
deficiency is partially understood. Recently, Gielen et al. observed an upregulation of
supressor of cytokine signalling (SOCS), an inhibitor of IFN-I production, in bronchial
epithelial cells of asthmatic patients.66
Likewise, Gill et al.67 compared the induction of IFN-a by influenza virus in pDCs
isolated from patients with asthma or healthy subjects and found that influenza virus
infection promoted significantly less IFN-α secretion by pDCs from patients with
asthma patients.
It has been suggested that the reduction in IFN-αβ secretion during upper
respiratory viral infections may lead to exacerbated lung pathology in those with
asthma because of the inability of innate secretion of IFN-αβ to control viral
replication in the lungs.63
IgE cross-linking significantly reduced TLR9 expression, resulting in decreased
IFN-α production in response to CpG DNA. These results are intriguing because they
suggest that sensitization with allergens may block IFN-α secretion during viral
infections. Moreover, Gill et al. 67 demonstrated that IgE, but not IgG, cross-linking
significantly reduced IFN-α secretion from pDCs in response to both influenza A and
B virus infection.
Type I IFNs elicit different mechanisms that may be protective from exaggerated
Th2/IgE responses. IFN-αβ promotes IL-21 secretion, which is reported to negatively
regulate both IgE production and allergic rhinitis.68-70 These findings are supported by
early studies demonstrating that IFN-αβ can suppress IgE class switching during B-
cell priming.71, 72
Huber et al. found that type I IFNs block GATA-3 activation and, in turn, Th2
development. In the same manner, they inhibit cytokine secretion from committed
Th2 cells. 73 An additional mechanism for dampening Th2 responses is IFNbeta-
mediated upregulation of IL13R-alpha2 expression in primary fibroblasts with
functional consequences in allergic reactions. Since this alternative IL-13 receptor
does not induce the typical Th2 effects of this cytokine, stimulation of IFN-beta
production by dsRNA was accompanied by a reduction of eotaxin expression.74
IFNAR-deficient mice and inactivated IFN-β gene mice In the beginning of 1990s, mice models lacking the type I IFN-α/β receptor (A
129)1, type II IFN-γ receptor (G 129)75 or both types of IFN receptors (AG 129) were
first developed.76
IFNAR-deficient mice are completely unresponsive to type I IFNs. These mice
show no overt anomalies but are unable to cope with viral infections1 and they are
more vulnerable to develop autoimmune disease of the central nervous system
(CNS).77
Lena Erlandsson et al. generated a mouse strain with an inactivated IFN-β gene in
1998.78 The mice produce neither IFN-β nor IFN-α upon Sendai virus infection. The
heterologous sequences were grafted onto the IFN-β coding sequence, eliminating
the region encoding the first 4 amino acids and no expression of the IFN-β protein
was detected from the modified locus.
IFN-Discovery and structureThe unique member of the type II interferon family, IFN-, was first identified in the
1960s for its distinctive antiviral activity against the Sindbis virus in human leukocyte
cultures. 79 Both human and mouse IFN- proteins are encoded by a single gene
copy. The human IFNG gene is located on chromosome 12 and mouse gene on
chromosome 10. 80-82 Interestingly, IL-22 is located in close vicinity of the IFNG gene
into the same genomic locus both in human and mouse. Despite the fact that the
genomic structure of the IFNG gene is highly conserved among vertebrates and
consists of 4 exons and 3 introns, the interaction of IFN and its receptor is species-
specific and is restricted to the receptor extracellular domains. The human IFN-
protein precursor contains 166 residues and includes a cleavable hydrophobic signal
sequence of 23 amino acids. An active form of the IFN protein is 34kDa homodimer
that is formed by anti-parallel inter-locking of the two monomers, each consisting of a
core of six α-helices and an extended unfolded sequence in the C-terminal region. 83-
85
Receptor and signalingActive homodimer of IFN- interacts with heterodimeric receptor consisting of
ligand-binding chains, designated as IFNGR1 or IFNGR , and signal-transducing
chains, known as IFNGR2 or IFNGR with a 1:2:2 stochiometry. 86, 87 The IFNGR1
and IFNGR2 genes are located on chromosome 6 and chromosome 21 in human
and on chromosome 10 and 16 in mouse, respectively. 85, 86, 88 Both chains belong to
the class II cytokine receptor family and IFNGR2 is usually the limiting factor in IFN
responsiveness, since the IFNGR1 chain appears to be constitutively expressed. Due
to the lack of intrinsic kinase or phosphatase activity, the IFNGR1 chain is
persistently associated to JAK1 and the IFNGR2 chain to JAK2, in order to assure
the signal transduction. IFN signaling leads to the phosphorylation and
homodimerization of the STAT1 protein, translocation of the homodimer into the
nucleus, and its binding to the promoters containing a defined gamma activated site
(GAS) to initiate the transcription. Interferon regulation factors (IRF) family members,
including IRF-1, IRF-2, IRF-7 and IRF-9 are also involved in IFN signaling.89-92 In
addition, coordination and cooperation of multiple distinct signaling pathways,
including the mitogen-activated protein kinase p38 cascade, phosphatidylinositol 3-
kinase (PI3K) cascade and ATF6-C/EBP- signaling pathway are needed for
generation of appropriate cellular response to IFN 93, 94 On the other hand,
IFN appears to suppress other signaling pathways, such as activation via IL-4, IL6
and TGF receptors and TLRs. 95
A recent study has shown that IFN- signaling also primes promoter and enhancer
regions genome wide via inducing histone acetylation. This effect is mediated
through genome wide occupation of transcription factor binding regions by activated
STAT1 and IRF-1. This priming of chromatin encompasses the key inflammatory
cytokine genes TNF, IL6 and IL12B, demonstrating an important role for IFN-γ
signaling an epigenetic function for augmenting TLR responses. 96
Cellular sources and regulationIn contrast to type I interferons, which can be expressed by all cells, the
expression of IFN-γ is restricted to certain immune cells. 93 Number of cell population
from both the innate (e.g. NK cells, NKT cells, macrophages, myelomonocytic cells)
and adaptive immune systems (e.g. Th1 cells, CTL and B cells) can secrete IFN-. Its
production is controlled by APCs-secreted cytokines, mainly IL-12 and IL18. IL-12
promotes the secretion of IFN in NK cells and the combination of IL-12 and IL-18
further increases IFN- production in macrophages, NK cells and T cells. The Th2
inducing cytokine IL4, as well as IL-10, TGF- and glucocorticoids, negatively
regulate the production of IFN- 97
The expression of IFN- is tightly regulated. The promoter and introns of the IFN-
gene contain binding sites for ATF-2, NF-B, AP-1, YY1, NF-AT, STAT and T-box
type transcription factors. 98 In Th1 and NK cells, T-bet, a transcription factor
responsible for Th1 commitment is important for production of IFN-98 However, T-bet
also recruits Bcl-6 to the IFN- locus, which suppresses IFN-expression in late
stages of Th1 differentiation, possibly to prevent the overproduction of IFN-99In
CD8 T cells, T-bet apparently does not influence expression of IFN-Instead, a
transcription factor NFAT1 up-regulates IFN- production after activation via TCR. 100
However, another study demonstrates that T-bet and Runx3 transcription factors
cooperatively regulate IFN-γ production CD8+ T cells. 101 In NK cells, inhibitor of κB-ζ
(IκBζ), a Toll-like receptor (TLR)/ interleukin-1 receptor (IL-1R) inducible transcription
factor is a necessary factor that directly binds to IFN promoter and regulates its
production in response to stimulation by IL-12/IL-18. 102 As recently demonstrated in
T-bet-ZsGreen reporter mouse strain, IL-12 induces transcription factor T-bet and
STAT4 and this is critical for IFN- production and Th1 responses in mice infected with
Toxoplasma gondii. 103 Another negative regulator, Twist1, forms complex with Runx3
and abolishes Runx3 and T-bet binding at the Ifng locus and IFN-γ production. 104
In addition, the IFN- gene locus in controlled by epigenetic modifications and IFN-
production is regulated via post-transcriptional mechanisms. For instance, very
recent study demonstrates that histone methylase SUV39H1, which participates in
the trimethylation of histone H3 on lysine 9, a modification that leads to transcriptional
silencing, is important for silencing of the IFN- gene and other Th1 loci, ensuring Th2
lineage stability. 105 Another study shows that IFN-mRNA is destabilized by RNA-
binding protein Tristetraproline (TTP) and this results in reduced production of IFN-
106 Recently; it has been also shown that miR-29 controls the level of IFN- by
direct targeting of IFNmRNA. 107
Role in immune regulation and cellular networksAs a member of the interferon family, IFN- is one of the most potent cytokines for
mobilizing antimicrobial effector functions against intracellular pathogens. IFN-
exerts its antiviral effects mainly via the induction of key antiviral enzymes including
the double stranded RNA activated protein kinase (PKR), 2’-5’ oligoadenylate
synthetase (2-5 synthetase) and the ds RNA specific adenosine deaminase (dsRAD). 108-110 In contrast to type I interferon response that is triggered directly by viral
infection, IFN- rather acts as a secondary mediator and the immunomodulatory
activities of IFN- are also important during the development of adaptive immune
response for the establishment of an antiviral state.
IFN- coordinates a broad range of biological functions. As the major product of
fully differentiated Th1 cells, IFN- promotes cytotoxic activity by both direct and
indirect mechanisms. Directly, together with IL-12 and IL-27, IFN- participates in the
events taking place during the commitment of naïve CD4+ T cells towards a Th1
phenotype.111 Indirectly, IFN- can regulate antigen processing, and via its ability to
inhibit cell growth, IFN- can reduce the Th2 cell population, and thus, contribute to
the Th1 cell differentiation.
Another important physiological role of IFN-is its capability to up-regulate MHC
class I and II proteins and the related factors, which is compulsory for the recognition
of infected cells by the immune system. Within the class I antigen-presentation
pathway, IFN- induces expression of new proteasome subunits, LMP2, MECL-1 and
LMP7, to form an inducible proteasome. This is a mechanism by which IFN- can
increase the quantity, the quality and the repertoire of peptides for class I MHC
loading. 111 IFN- also induces the proteasome regulator PA28, which associates with
the proteasome and alters proteolytic cleavage preference and allows more efficient
generation of TAP- and MHC- compatible peptides to increase the overall efficiency
of class I MHC peptide delivery. 112 In addition to inducing TAP transporter that is vital
for the transport of the peptide from the cytosol to the ER lumen, IFN- also up-
regulated class I MHC complex. 113
IFN- can also promote activation of CD4+T cells via up-regulation of class II
antigen-presenting pathway in professional and non-professional APCs. By inducing
the expression of several key proteins, IFN- up-regulates the quantity of
peptide:MHC class II complexes on the surface of the cell. Among these, there is the
constituents of the MHC complex itself, lysosomal proteases cathepsins B, H and L
that are implicated in peptide production, DMA and DMB that function to remove
CLIP from the peptide binding cleft to render it available to peptide loading, and a key
transcription factor for the regulation of expression of genes involved in the MHC II
complex, class II transactivator (CIITA). 114-116
Other important features of IFN- are the inhibition of cell growth and capability to
induce cell death. IFNs inhibit proliferation primarily by increasing protein levels of
cyclin-dependent kinase inhibitors (CKI) of the Cip/Kip family. IFN- induces the CKI
p21 and p27 that inhibits the activity of CDK2 and CDK4, respectively, causing the
cell cycle to arrest at the G1/S checkpoint.117-120 IFN- treatment of cells bearing high
levels of IFNGR can induce apoptosis in an IRF-1 dependent manner via activation of
IL-1-converting enzyme caspase-1.121 IFN- also induces a number of other pro-
apoptotic proteins, including the antiviral enzyme PKR, the death associated DAP
factors and cathepsin D. IFN- may enhance cell sensitivity to apoptosis by
increasing the surface expression of Fas/Fas ligand and of the TNF-receptor. 122-124
Concordantly, IFN- is capable of modulating the immune responses by controlling
activation-induced cell death (AICD) of CD4+ T cells through signaling via the death
receptor Fas. 125 CD4+ T-cells that lack IFN- or STAT1 are resistant to AICD and
IFN- was proposed to increase CD4+ T-cells apoptosis through a mitochondrial
pathway, which requires the production of caspases.126 Retrovirus-mediated
expression of caspase-8 could restore the sensitivity of Stat1-deficient T-cells to
AICD.125 However, a recent study challenged this mechanism of action of IFN- by
showing a function for IFN- in controlling CD4+ T cell death in ways that do not seem
to involve Fas or its ligand and neither to require the production of caspases.127 This
study suggests that mycobacterial infection-induced CD4+ T cell death occurs due to
autophagy and that Irgm1, also called LRG47, is an interferon-inducible GTPase that
seems to suppress IFN--induced autophagy in CD4+ T cells. The expression of
several members of the family of the anti-apoptotic protein Bcl-2 was not affected by
either IFN- or the absence of Irgm1, which suggests a lack of involvement of the
mitochondrial cell death pathway.
Production of IFN- by activated monocytes also significantly upregulates TRAIL
receptors of NK cells, increasing the cytotoxicity of tumour localized NK cells against
TRAIL-sensitive tumour cells; such as breast cancer or prostate cancer. 128 IFN- can
also contribute to cancer pathogenesis by affecting cell proliferation. A recent study
has shown that IFN-γ secreted by cytotoxic T cells contributes significantly to the
proliferation of chronic myeloid leukemia stem cells (LSCs). Additionally, inhibitory
molecules PD-L1 and PD-L2 are upregulated on LSCs in response to IFN-γ
signaling; contributing to the immune escape capabilities of LSCs. 129 IFN-γ
stimulation also results in PD-L1 upregulation on neutrophils, which allows PD-L1
mediated suppression of lymphocyte proliferation by neutrophils during bacterial
infections. This is the first in vitro study documenting an immunosuppressive
capability of IFN-γ. 130
In addition to its role in the development of a Th1-type response, IFN- plays a role
in the regulation of local leukocyte-endothelial interactions. IFN- regulates this
process by up-regulating expression of numerous chemoattractant (e.g., IP-10, MCP-
1, MIG, MIP-1a/b and RANTES) and adhesion molecules (e.g., ICAM-1 and VCAM-
1). 131-135 Moreover, IFN- causes major changes in gene expression program in
epithelial cells influencing the expression of up to several thousands of genes. For
instance, 3530 genes were reported to be differentially expressed in human IFN-
treatedkeratinocytes compared to non-treated cells, whereas more than 800
genes were induced more than 2-fold. 136
IFN- was originally called ‘macrophage activated factor’, and enhanced microbial
killing ability is observed in IFN- treated macrophages. IFN- induces the anti-
microbial function of macrophages and neutrophiles by induction of the NADPH-
dependent phagocyte oxidase (NADPH oxidase) system (called "respiratory burst"),
production of NO intermediates, tryptophan depletion, and up-regulation of lysosomal
enzymes. 137, 138 IFN- can effectively prime macrophages to respond to LPS and
other TLR agonists since TLR4 transcription and subsequent surface expression are
increased by IFN-. LPS-dependent signaling is enhanced by IFN- via the induction
of MD-2 accessory molecule, MyD88 adaptor, and IRAK expression. 139, 140 IFN- was
recently identified as a modulator of the cooperation between TLR and Notch
pathways. By inhibiting Notch2 signaling and downstream transcription, IFN-
abrogates Notch-dependent TLR-inducible genes, which represents another means
how IFN- can modulate effector functions in macrophages. 141
Functions as demonstrated in transgenic miceDespite the important functions of IFN- in the immune system, both Ifn- -/- and
Ifngr-/- mice showed no obvious developmental defects and their immune system
appeared to develop normally. 75 However, these mice show deficiencies in natural
resistance to several bacterial, parasitic, and viral infections. Ifn--/- mice are
characterized by suppressed splenic NK cells activity, uncontrolled splenocyte
proliferation, reduced expression of the MHCII proteins and antimicrobial factors in
macrophages. Ifngr-/- mice show a deficiency in IgG2a production, increased
susceptibility to vaccinia virus, Listeria monocytogenes, pseudorabies virus,
Mycobacterium bovis and increased resistance to endotoxic shock. 142-146 Localized
site inflammation, lymphocyte infiltration and severe tissue destruction has been
observed in transgenic mice overproducing IFN-, such as Socs1-/- and miR-146a-/-
mice. 147, 148 By using the sanroque mouse model of lupus, it has been shown that
decreased Ifng mRNA decay caused excessive IFN signaling in T cells and led to
accumulation of follicular T cells, spontaneous autoantibody formation, and nephritis. 69
Role of IFN- in human diseases
Because IFN-g is a multipotent cytokine that plays an important role in both the innate
and the adaptive immune response, it is not surprising that its deficiency is associated
with the pathogenesis of several diseases. Therefore, use of bioengineered IFN-γ
(Actimmune) is common clinical strategy for treatment of chronic granulomatous
disease149 and osteopetrosis.150 Moreover it has been shown to be effective in atopic
dermatitis treatment151 and is tested in clinical trials for Friedreich's Ataxia, 152, 153
Pulmonary Fibrosis,154-156 among others. On the other hand, IFN-γ neutralization by
using humanized mAbs (Fontolizumab) is a clinical strategy for treatment of Crohn’s
disease 157. Additionally, Fontolizumab was tested in phase 2 clinical trials for potential
use in rheumatoid artritis, however the study was terminated.62
Low levels of IFN- correlate with an increased susceptibility to intracellular
pathogen infection with subsequent tissue destruction, as well as tumour
development. Patients with acquired IFN- deficiency; which is caused by serum
auto-antibodies that specifically neutralized the biological activity of IFN-, show
defects in the Th1-cytokine pathway together with disseminated tuberculosis and non
tuberculous mycobacterial infections. 158-161 On the other hand, early IFN- production
in response to live parasite stimulation correlates with a protective immunity to
symptomatic malaria in Papua New Guinean children. 162
IFN- may also play an important role in the pathogenesis of type 1 diabetes as
suggested by the decreased levels of IFN- were observed in newly diagnosed
diabetic patients.163 The cellular arm of the immune system is implicated in the
pathogenesis of the disease and diabetes can be induced by the transfer of Th1 CD4+
T-cells expressing cytokine in a non-obese mouse model of autoimmune diabetes
(NOD). Decreased apoptosis of activated T-cells in NOD mice is a feature or the
outcome of the loss of IFN--mediated immune suppression. 164
Depending on cellular environment, IFN- can either induce or restrict the
development of autoimmunity. For instance, arthritis onset and severity are reduced
under conditions, where IFN- is neutralized or in mice deficient in IFN-, suggesting
a role of IFN- in the initiation of the disease. 165 In another model of autoimmune
disease, in experimental autoimmune encephalomyelitis (EAE), the disease is
enhanced in IFN--deficient mice. 166, 167 IFN- can also inhibit the inflammatory
process at a later stage of the disease and it was proposed that this was due to the
ability of IFN- to suppress IL-17 secretion. However, it seems that IL-17 production
is dispensable for the exacerbation of the disease and that IFN- mediates this
inhibition via its anti-proliferative and pro-apoptotic effects on activated T-cells. 166, 168
Since the biological effects of IFN- are widespread, the polymorphisms in the IFN-
or IFNGR genes have been shown to be associated with susceptibility to several
diseases, including pulmonary tuberculosis, multiple sclerosis, myasthenia gravis and
arthritis manifestation. In addition, mutation in the IFN- gene has been shown to
lower the body’s ability to resist mycobacterial infection. 169
Complete IFNGR1 deficiency is due to homozygous recessive mutations or to
heterozygous mutations affecting the extracellular domain of the IFNGR1 protein and
preventing the expression of the receptor at the cell surface.170 In the patients with
mutations in IFNGR2, the cell surface expression of IFNGR1 is normal, but functional
response to IFN- is lacking. 171, 172 Individuals with mutations in the human IFNGR1
or IFNGR2 genes that lead to defective expression or function of the IFN- receptor,
show severe susceptibility to poorly virulent mycobacteria and often acquire a
bacillus Callmette-Guerin infection. 173
Development of allergic diseases and atopic state have been associated with poor
function of IFN-or the receptors. Gene variants of IFN- and IFNGR1 have been
shown to be associated with atopic dermatitis complicated by Eczema Herpeticum. 174
Concordantly, DCs from patients with atopic dermatitis have reduced IFN- receptor
expression and attenuated IFN- response. 175 It has been proposed that Th2
dominance in atopic patients is caused by selective activation-induced cell death of
high IFN--secreting Th1 cells in peripheral blood that skews the immune response
towards surviving Th2 cells. 176 In asthma, IFN-γ expression in airways was found to
be a strong distinguishing factor for aspirin-tolerant asthma and aspirin-exacerbated
respiratory disease (AERD). AERD is characterized by a high expression of IFN-γ in
comparison to aspirin-tolerant asthma, alongside a Th2 cytokine profile.
Immunohistochemistry staining showed that the main source of IFN-γ in AERD to be
eosinophils. 177 The expression of IFN-γ in airways contributes significantly to
upregulation of CysLT production by eosinophils infiltrating airway tissue in AERD
patients and leads to increased severity of its inflammatory features.177 Pro-
inflammatory effects of IFN-γ in asthmatic lung are counter balanced by IL-22; and IL-
22 is capable of decreasing IFN-γ-induced CCL5/RANTES, as well as MHC I, MHCII
and ICAM-1 in asthmatic lung epithelial cells. 178
Similarly to autoimmunity related chronic tissue inflammation, enhanced level of
IFN- appears to influence inflammatory processes in the epithelial cells in the
chronic phase of allergic inflammation, whereas IFN- most probably is the main
cytokine responsible for eczema formation in atopic dermatitis causing apoptosis of
keratinocytes. 179-183 IFN- also plays role in chronic epithelial inflammation related to
asthma and chronic sinusitis. 184
TNFαDiscovery and structureThe history of tumor necrosis factor α (TNF-α) begins at the end of the 19 th
century, when Dr. William B. Coley used a bacterial extract of heat-killed
Streptococcus pyogenes and Serratia marcescens to induce tumor necrosis in
sarcoma patients.185, 186 Variations of this formula, later known as Coley’s toxins and
representing one of the first forms of immunotherapy, were in use for treatment of
various types of cancer until mid-20th century with more or less success. In
accordance with previous observations in patients with spontaneously regressing
tumors, the regression of tumors in patients receiving Coley's toxins was
accompanied by a severe systemic inflammatory reaction. Today we know that one
of the key inflammatory molecules causing this reaction was TNF-α. Identified in
1975, this cytokine was first described as TNF, a protein factor in the serum of mice
infected with bacillus Calmette-Guérin (BCG) and treated with LPS that caused
hemorrhagic necrosis of different transplanted tumors in vivo and cytolysis of a
mouse fibrosarcoma cell line in vitro.187 Several years later the protein inducing
wasting (cachexia) and septic shock in mice was purified from the supernatant of
endotoxin-treated macrophages.188-190 This protein, at the time named cachectin, was
soon revealed to be identical to TNF-α.191
In 1985 human TNF-α gene was cloned and expressed.192-195 It is located in region
6p21.3 of chromosome 6 as a single copy 3-kb gene consisting of 4 exons. Its
promoter region contains several binding sites for the transcription factor nuclear
factor kappa B (NF-κB). TNF-α exists as two protein forms associating into
homotrimers196: the 26-kd membrane-bound form (mTNF-α), a type II integral
membrane protein, and the 17-kd soluble form (sTNF-α).197 sTNF-α is generated by
proteolytic cleavage of mTNF-α mainly by TNF-α converting enzyme (TACE,
ADAM17)198 at the cell surface. If not emphasized otherwise, TNF-α usually refers to
the soluble form of this cytokine.
Cloning of lymphotoxin (LT) and TNF cDNAs revealed structural and functional
homology between the two proteins. This led to the renaming of TNF to TNF-α and
LT to TNF-β. Along the same line, LT-β was renamed to TNF-C. Today these
alternative names for LTs are not frequently used and there are opinions that TNF-α
should again be called by its original name TNF.
Receptor and signalingTNF-α binds specifically to two cell-surface receptors: TNFR1 (p55/60, CD120a)
and TNFR2 (p75/80, CD120b), two structurally related, but functionally somewhat
distinct receptors. They are single transmembrane glycoproteins with elongated
extracellular domains containing four cysteine-rich repeat motifs. Each of the two
receptors binds both mTNF-α and sTNF-α. However, TNFR1 can be fully activated
by both mTNF-α and sTNF-α, while TNFR2 can only be efficiently activated by
mTNF-α. Upon interaction with their ligands, both TNFR1 and TNFR2 form a
homotrimer, which initiates subsequent signaling pathways. Intracellular regions of
TNFR1 and TNFR2 differ significantly, suggesting that the two TNFRs signal through
distinct molecular interactions.
Signaling through TNFR1 is mainly associated with pro-inflammatory, cytotoxic
and apoptotic responses and plays a critical role in host defense against microbes
and their pathogenic factors. Upon receptor-ligand binding the death domain of
TNFR1 interacts with TNF receptor-associated death domain (TRADD) adapter
protein. Following TRADD activation, three pathways can be initiated199-201: apoptotic,
NF-κB or MAPK/AP-1 pathway. In case of programmed cell death pathway initiation,
TRADD recruits downstream Fas-associated death domain (FADD) adapter protein
and initiates the signaling pathway leading to recruitment and activation of proteins of
the caspase cascade (caspase 8, caspase 10 and effector caspases). However,
apoptosis induced by TNF-α plays only a minor role in the repertoire span of TNFR1,
especially compared to the strong inflammatory response it can trigger, and is often
masked by anti-apoptotic effects of NF-κB activation. When initiating a
pro-inflammatory cascade, TRADD recruits two types of adapter molecules, the
receptor interacting protein (RIP) and the TNF receptor-associated factors (TRAFs),
which initiate the signaling cascade leading to the activation of gene transcription via
transcription factors NF-κB and AP-1. Some of the genes whose transcription is
activated include molecules important for cell survival, proliferation and
differentiation, pro-inflammatory cytokines and chemokines, growth factors and TNF-
α itself. There is an extensive cross-talk between these two opposite pathways, one
of them leading to programmed cell death and the other to cell activation and potent
inflammatory response. For instance, NF-κB enhances the transcription of inhibitory
proteins that interfere with the apoptotic pathway and on the other hand, activated
caspases cleave several components of the NF-κB pathway. The fine balance
between the two pathways can be shifted towards one or the other by many factors,
such as cell type, cytokine stimulation etc. Further, recent studies have shown that
there is another programmed death pathway, necroptosis, depending on activity of
TGF-β–activated kinase 1 (TAK1) and RIP kinase 3 (RIPK3).202-204 The result of such
finely tuned cross-connection between the two complex signaling pathways is the
appropriate response of various cell types and conditions harboring diverse functions
upon TNF-α release in inflammation.
For a long time the importance of TNFR2 signaling was rather neglected in favor of
TNFR1, but recently its role is ever more acknowledged. It is now known that
although it plays a role in both, TNF-α-induced cell activation and TNF-α-induced
apoptosis, it is still mainly associated with cellular activation, proliferation and
migration. Because it requires mTNF-α binding for activation, it plays an important
role in TNF-α signaling in cell-to-cell contact, a fact which was very often neglected
because of routine use of sTNF-α as cell culture stimulus in lab conditions. Since it
has no death domain, TNFR2 typically engages TRAFs directly, which then leads to
the activation of NF-κB and AP-1. In mediating apoptosis it also does it directly
through interaction with RIP leading to the activation of caspase cascade.
As a mechanism to keep inflammation under control, extracellular portions of
TNFRs can be released from the cell surface upon cell activation or injury. The
soluble TNFRs, which retain the property of binding TNF-α, can then dampen the
TNF-α activity by competing for TNF-α binding with the TNFRs associated to the cell
membrane and thus neutralizing excess TNF-α.
Cellular sources and targetsMany potentially harmful stimuli of physical, chemical, or immunologic nature have
the potential to induce rapid TNF-α expression. The most common inducers of TNF-α
expression are LPS and other substances of microbial origin, detected by innate
immune receptors such as TLRs. TNF-α is mainly produced by activated
macrophages, but can also be produced by other immune cell types, such as
monocytes, CD4+ T-lymphocytes, B-lymphocytes, neutrophils, NK cells and mast
cells. It can also be produced by non-immune cells, such as fibroblasts, astrocytes,
cell proliferation and goblet cell mucus production in SMAD3 -/- mice or after blockage
of TGFβ,373-375 while in a HDM model SMAD3-/- mice had comparable remodeling to wt
mice.376 Patients treated for 2 months with anti-IL-5 had not only reduced tissue
eosinophilia but also reduced TGFβ levels and ECM deposition.377 IL-5 knockout
mice showed a comparable phenotype.378 Airway remodeling by TGFβ seems to be
insensitive to corticosteroid treatment.379 TGFβ induces a big variety of changes
leading to airway remodeling. It induces epithelial apoptosis and in presence of the
cell stress in the lungs leads to detachment of epithelial cells. Epithelial cells in
asthmatics further undergo EMT under the influence of TGFβ. Subcellular fibrosis is
orchestrated by TGFβ by increased ECM deposition and increased fibroblast
proliferation, increased myofibroblast differentiation and increased factor secretion
from fibroblasts further accelerating fibrosis. TGFβ also increases smooth muscle cell
proliferation and migration, increases mucus secretion by goblet cells and increases
angiogenesis by the enhanced release of pro-angiogenic factors like VEGF.380
Due to the controversial role of TGFβ in asthma Yang et al. proposed a two-step
model where an early deficiency in Tregs and possibly TGFβ lead to a Th2 driven
airway inflammation, eosinophilic infiltration and following to that an increase in
TGFβ. A continued deficiency of Tregs and their effector function, possibly by
inefficient suppression of Th2 immune responses,381, 382 results in airway remodeling
by TGFβ while it still can not suppress the immune response. The paradoxical effect
of TGFβ on the pathogenesis of asthma by inducing airway remodeling and fibrosis
as well as T-cell tolerance at the same time is an interesting phenomenon and
requires further research.383 In atopic dermatitis (AD) there was no difference of
TGFβ levels found in between lesional and non-lesional skin384 In association studies
however there was a link between a low TGFβ producing polymorphism and AD.385
SMAD3-/- mice show a decreased skin inflammation in a mouse model of AD, but an
increase in mast cells together with an increase in specific IgE386 and TGFβ
application can suppress AD like skin lesions in a mouse model.387 TGFβ was also
implicated in ECM deposition and skin remodeling in AD.388 Initially, there was an
absence of Foxp3+ Tregs described in AD lesions while Tr1 cells were present. None
of the both Treg subsets was able to suppress cytokine induced apoptosis in vitro.389
But other groups described the presence of Foxp3+ Tregs.390, 391 Similar to the findings
in skin, results in peripheral blood are controversial. While some studies found an
increase in Tregs, which correlated with disease activity, others could not observe
any differences.392-394 The observed differences might be explained by differences in
disease stage and treatment of the patients.
TGFβ plays also a role in allergic rhinitis. Although there was no difference in
TGFβ, observable levels of TGFβ receptors were increased in allergic rhinitis.395 A
polymorphism in TGFβ 1 was also associated with the risk of developing allergic
rhinitis.396 Serum TGFβ levels were found to be increased during pollen season and
even higher after specific immunotherapy.397 The increased levels of TGFβ might
increase the chemotaxis of mast cells to the site of allergic inflammation.398 Chronic
rhinosinusitis is associated with allergy development and TGFβ plays a major role in
its development, and has been extensively reviewed lately.399 In eosinophilic
esophagitis, phospholamban is regulated by TGFβ1, and it might provide a novel
therapeutic target to improve esophageal dysmotility and clinical dysphagia.400
TGFβ is essential in maintaining food tolerance directly and by controlling Treg
induction and being part of Treg function401 and thus control immune response and
IgA production in the gastrointestinal tract. CD5+CD19+CX3CR1+ tolerogenic B cells
are capable of inducing Tregs in the intestine and suppress food allergy-related Th2
pattern inflammation in mice.402 Orally administered TGFβ is active and can suppress
allergic immune response and induce tolerance.403, 404 TGFβ is contained in breast
milk and might this way be important in the allergen tolerance during early life.405
Functions as demonstrated in TGFβ-deleted mice, receptor-deficient mice, human mutations and therapeutic applications
TGFβ knockout mice show isotype specific phenotypes. 50% of the TGFβ 1
knockout mice die in utero and it is postnatally lethal for the other newborns. The
mice die from multiorgan autoimmunity.325, 326 The deficiency in immune response
containment is mainly due to a missing TGFβ signaling to T cells, resulting in
autoimmunity, CD4 T cell activation, especially Th1 cells, decreased CD8+ cytotoxic
lymphocyte differentiation and lack of NKT cells.406, 407 Thrombospondin deficient mice
exhibit a similar phenotype to TGFβ 1 knockout mice due a deficiency in activating
TGFβ.408
The TGFβ 2 knockout is perinatally lethal. These mice show no signs of
autoimmunity, so they have no overlapping phenotype with TGFβ 1. TGFβ 2 deficient
mice have defects in heart and skeletal development, the eye and inner ear, the
urogenital tract, and are not viable after birth.409 TGFβ 3 knockout mice do neither
show an autoimmune phenotype, but a failure of closing of the palate shelves leaving
a palatal cleft without further craniofacial abnormalities. The mice have also a
consistent delay in pulmonary development, and they die within 1 day after birth. 410, 411
Knockout of the Tβ-II in mesenchymal stem cell lead to less development of
osteoarthritis, suggesting that TGFβ1 in subchondral bone seem to initiate the
pathological changes of osteoarthritis.412
For humans there is no description of TGFβ isoform mutations with a complete
loss of function. Regarding the results from the knockout mice these mutations might
not be viable. Several different mutations in TGFβ 1 lead to an increase in TGFβ
activity. This autosomal dominant syndrome, called Camurati-Engelmann disease,
displays a progressive diaphyseal dysplasia characterized by hyperostosis and
sclerosis of the long bones.413, 414 Patients with a haploinsufficient for TGFβ 2 suffer
from the autosomal dominant Loeys-Dietz syndrome type 4. They develop aortic
aneurysm, aortic dissection, intracranial aneurysm and subarachnoidal
hemorrhage.415, 416 In addition, patients with Loeys-Dietz syndrome are strongly
predisposed to develop allergic diseases, including asthma, food allergy, eczema,
allergic rhinitis, and eosinophilic gastrointestinal disease.417 T cells from patients with
this syndrome has increased phosphorylation of SMAD2 and SMAD3 in response to
TGFβ, which suggests that TGFβ receptor signaling is enhanced, rather than
repressed, in these individuals.417 Mice with a haploinsufficiency of TGFβ 2 display
similar defects like human patients.415 Mutations in the 5-prime or 3-prime UTR of
TGFβ 3 causing an increase in activity of TGFβ 3 lead to arrhytmogenic right
ventricular dysplasia type 1, an autosomal dominant disease with reduced
penetrance. Usually the arrhytmias are well tolerated, but they are also one of the
major genetic causes of sudden juvenile death.418, 419
Haploinsufficiency caused by mutations in the receptor genes TGFBR1 and
TGFBR2 lead to Loeys-Dietz syndrome type 1A and 2A, respectively type 1B and 2B.
As described for TGFβ 2, it is an aortic aneurysm syndrome here accompanied with
arterial tortuosity, and bifid uvula. Type 1 patients have craniofacial involvements like
cleft palate, craniosynostosis and hypertelorism, why only some type 2 patients have
a bifid uvula. Patients with this syndrome show a high rate of pregnancy related
complications.420 In addition to the Loeys-Dietz syndrome, germline and somatic
missense mutations in TGFBR2 can result in hereditary nonpolyposis colorectal
cancer-6.421
Due to its involvement in many diseases, TGFβ is targeted for therapeutic use in
many clinical trials. The TGFβ blocker target almost every step in the TGFβ pathway:
expression, activation, receptor binding and signaling. Different approaches to target
TGFβ are used, including antisense nucleotides, ligand competitive peptides, small
molecular inhibitors against the receptor kinase and antibodies against ligands,
receptors or associated proteins. The main disease groups targeted are cancer
therapy, fibrosis, scleroderma, restenosis following artery bypass and angioplastic,
and postoperative scaring in ocular conditions.276 Since TGFβ has multiple functions
in cancer pathology targeting TGFβ can also have several beneficial effects. For
example, blocking TGFβ during radiation therapy of breast cancer can increase
immune response and decrease cancer progression and metastasis. At the same
time it can diminish therapy induced fibrosis.422 Marfan syndrome is accompanied by
elevated levels of TGFβ due to the decreased binding of TGFβ to the ECM. Vascular
symptoms in Marfan syndrome might be alleviated by blocking of TGFβ 284, 285 and
there are clinical trials now in phase II. 276 The perinatal blocking might also relief the
distal airspace enlargement in lungs by preventing apoptosis in the developing lung. 285 Concomitantly, TGFβ blocking might further improve muscle function and repair in
both Marfan syndrome and Duchenne muscular dystrophy. 423
In total there are so far 106 SNPs and 11 other variations described for TGFβ 1
and it’s downstream signaling, with ethnical differences.424 TGFβ 2 and TGFβ 3
display additional. It’s not difficult to imagine that these variations are associated with
different susceptibilities to a large variety of diseases.
References
1. Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, et al. Functional role of type I and type II interferons in antiviral defense. Science 1994; 264:1918-21.
2. Tomasello E, Pollet E, Vu Manh TP, Uze G, Dalod M. Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types. Front Immunol 2014; 5:526.
3. A. Isaacs JL. Virus interference: the interferon. Proc. R. Soc. Med. 1957; 147:258-67.
4. De Maeyer E, De Maeyer-Guignard J. Type I interferons. Int Rev Immunol 1998; 17:53-73.
5. Paul F, Pellegrini S, Uze G. IFNA2: The prototypic human alpha interferon. Gene 2015; 567:132-7.
6. Oritani K, Kincade PW, Zhang C, Tomiyama Y, Matsuzawa Y. Type I interferons and limitin: a comparison of structures, receptors, and functions. Cytokine Growth Factor Rev 2001; 12:337-48.
7. Bekisz J, Schmeisser H, Hernandez J, Goldman ND, Zoon KC. Human interferons alpha, beta and omega. Growth Factors 2004; 22:243-51.
8. Gribaudo G, Lembo D, Cavallo G, Landolfo S, Lengyel P. Interferon action: binding of viral RNA to the 40-kilodalton 2'-5'-oligoadenylate synthetase in interferon-treated HeLa cells infected with encephalomyocarditis virus. J Virol 1991; 65:1748-57.
9. Fekete T, Pazmandi K, Szabo A, Bacsi A, Koncz G, Rajnavolgyi E. The antiviral immune response in human conventional dendritic cells is controlled by the mammalian target of rapamycin. J Leukoc Biol 2014.
10. Livingstone M, Sikstrom K, Robert PA, Uze G, Larsson O, Pellegrini S. Assessment of mTOR-Dependent Translational Regulation of Interferon Stimulated Genes. PLoS One 2015; 10:e0133482.
11. Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A 1998; 95:15623-8.
12. Soh J, Donnelly RJ, Kotenko S, Mariano TM, Cook JR, Wang N, et al. Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell 1994; 76:793-802.
13. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998; 67:227-64.
14. Sekellick MJ, Marcus PI. Interferon induction by viruses. VIII. Vesicular stomatitis virus: [+/-]DI-011 particles induce interferon in the absence of standard virions. Virology 1982; 117:280-5.
15. Colonna M, Krug A, Cella M. Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol 2002; 14:373-9.
16. Coccia EM, Severa M, Giacomini E, Monneron D, Remoli ME, Julkunen I, et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol 2004; 34:796-805.
17. Swiecki M, Wang Y, Gilfillan S, Colonna M. Plasmacytoid dendritic cells contribute to systemic but not local antiviral responses to HSV infections. PLoS Pathog 2013; 9:e1003728.
18. Foster GRR, O., Ghouze, F., Schulte-Frohlinde. E., Testa, D., Liao, M.J., Stark,G.R., Leadbeater,L. and Thomas,H.C. Different relative activities of
human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency. J Interferon Cytokine Res. 1996:1027-33.
19. Han SJ, Melichar HJ, Coombes JL, Chan SW, Koshy AA, Boothroyd JC, et al. Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii. Immunol Cell Biol 2014.
20. Beiting DP. Protozoan parasites and type I interferons: a cold case reopened. Trends Parasitol 2014.
21. Claudio N, Dalet A, Gatti E, Pierre P. Mapping the crossroads of immune activation and cellular stress response pathways. EMBO J 2013; 32:1214-24.
22. Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F, Borrow P, et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 2002; 99:3263-71.
23. Santini SM, Di Pucchio T, Lapenta C, Parlato S, Logozzi M, Belardelli F. The natural alliance between type I interferon and dendritic cells and its role in linking innate and adaptive immunity. J Interferon Cytokine Res 2002; 22:1071-80.
24. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P, Haswell LE, et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 2003; 424:324-8.
25. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 5:730-7.
26. Broquet AH, Hirata Y, McAllister CS, Kagnoff MF. RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium. J Immunol 2011; 186:1618-26.
27. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 1995; 14:6095-106.
28. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 2008; 205:1601-10.
29. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, et al. 5'-Triphosphate RNA is the ligand for RIG-I. Science 2006; 314:994-7.
30. Miettinen M, Sareneva T, Julkunen I, Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2001; 2:349-55.
31. Stetson DB, Medzhitov R. Type I interferons in host defense. Immunity 2006; 25:373-81.
32. Barnes BJ, Moore PA, Pitha PM. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem 2001; 276:23382-90.
33. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, et al. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res 2013; 41:D1040-6.
34. Richer MJ, Pewe LL, Hancox LS, Hartwig SM, Varga SM, Harty JT. Inflammatory IL-15 is required for optimal memory T cell responses. J Clin Invest 2015.
35. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007; 26:503-17.
36. Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, et al. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 2003; 8:237-49.
37. O'Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, et al. Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 2004; 200:437-45.
38. Huber JP, Farrar JD. Regulation of effector and memory T-cell functions by type I interferon. Immunology 2011; 132:466-74.
39. Braun D, Caramalho I, Demengeot J. IFN-alpha/beta enhances BCR-dependent B cell responses. Int Immunol 2002; 14:411-9.
40. Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med 2003; 197:777-88.
41. Le Bon A, Schiavoni G, D'Agostino G, Gresser I, Belardelli F, Tough DF. Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 2001; 14:461-70.
42. Bogdan C, Mattner J, Schleicher U. The role of type I interferons in non-viral infections. Immunol Rev 2004; 202:33-48.
43. Sampson LL, Heuser J, Brown EJ. Cytokine regulation of complement receptor-mediated ingestion by mouse peritoneal macrophages. M-CSF and IL-4 activate phagocytosis by a common mechanism requiring autostimulation by IFN-beta. J Immunol 1991; 146:1005-13.
44. Swiecki M, Gilfillan S, Vermi W, Wang Y, Colonna M. Plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral NK and CD8(+) T cell accrual. Immunity 2010; 33:955-66.
45. Stifter SA, Feng CG. Interfering with immunity: detrimental role of type I IFNs during infection. J Immunol 2015; 194:2455-65.
46. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 2014; 345:679-84.
47. Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 1979; 301:5-8.
48. Vallin H, Perers A, Alm GV, Ronnblom L. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol 1999; 163:6306-13.
49. Bave U, Alm GV, Ronnblom L. The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer. J Immunol 2000; 165:3519-26.
50. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 2001; 294:1540-3.
51. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449:564-9.
52. Lande R, Chamilos G, Ganguly D, Demaria O, Frasca L, Durr S, et al. Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self-DNA. Eur J Immunol 2015; 45:203-13.
53. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011; 3:73ra19.
54. Schmidt NW, Jin F, Lande R, Curk T, Xian W, Lee C, et al. Liquid-crystalline ordering of antimicrobial peptide-DNA complexes controls TLR9 activation. Nat Mater 2015; 14:696-700.
55. Ioannou Y, Isenberg DA. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 2000; 43:1431-42.
56. Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, et al. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996; 25:283-91.
57. Reder AT, Feng X. Aberrant Type I Interferon Regulation in Autoimmunity: Opposite Directions in MS and SLE, Shaped by Evolution and Body Ecology. Front Immunol 2013; 4:281.
58. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 2001; 6:34-55.
59. Pockros PJ, Reindollar R, McHutchinson J, Reddy R, Wright T, Boyd DG, et al. The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients. J Viral Hepat 2003; 10:55-60.
60. Kimby E, Östenstad B, Brown P, Hagberg H, Erlanson M, Holte H, et al. Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. Leuk Lymphoma 2015; 56:2598-607.
61. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, et al. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012; 255:8-17.
62. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: http://www.ClinicalTrial.gov. Accessed 2 February, 2016.
63. Tversky JR, Le TV, Bieneman AP, Chichester KL, Hamilton RG, Schroeder JT. Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon-alpha via Toll-like receptor 9. Clin Exp Allergy 2008; 38:781-8.
65. Baraldo S, Contoli M, Bazzan E, Turato G, Padovani A, Marku B, et al. Deficient antiviral immune responses in childhood: Distinct roles of atopy and asthma. J Allergy Clin Immunol 2012; 130:1307-14.
66. Gielen V, Sykes A, Zhu J, Chan B, Macintyre J, Regamey N, et al. Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. J Allergy Clin Immunol 2015; 136:177-88 e11.
67. Gill MA, Bajwa G, George TA, Dong CC, Dougherty, II, Jiang N, et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol 2010; 184:5999-6006.
68. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2002; 298:1630-4.
69. Shang XZ, Ma KY, Radewonuk J, Li J, Song XY, Griswold DE, et al. IgE isotype switch and IgE production are enhanced in IL-21-deficient but not IFN-gamma-deficient mice in a Th2-biased response. Cell Immunol 2006; 241:66-74.
70. Hiromura Y, Kishida T, Nakano H, Hama T, Imanishi J, Hisa Y, et al. IL-21 administration into the nostril alleviates murine allergic rhinitis. J Immunol 2007; 179:7157-65.
71. Finkelman FD, Svetic A, Gresser I, Snapper C, Holmes J, Trotta PP, et al. Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice. J Exp Med 1991; 174:1179-88.
72. Pene J, Rousset F, Briere F, Chretien I, Bonnefoy JY, Spits H, et al. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A 1988; 85:6880-4.
73. Huber JP, Ramos HJ, Gill MA, Farrar JD. Cutting edge: Type I IFN reverses human Th2 commitment and stability by suppressing GATA3. J Immunol 2010; 185:813-7.
74. Campbell-Harding G, Sawkins H, Bedke N, Holgate ST, Davies DE, Andrews AL. The innate antiviral response upregulates IL-13 receptor alpha2 in bronchial fibroblasts. J Allergy Clin Immunol 2013; 131:849-55.
75. Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, et al. Immune response in mice that lack the interferon-gamma receptor. Science 1993; 259:1742-5.
76. van den Broek MF, Muller U, Huang S, Aguet M, Zinkernagel RM. Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors. J Virol 1995; 69:4792-6.
77. Kalinke U, Prinz M. Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS. Immunol Cell Biol 2012; 90:505-9.
78. Erlandsson L, Blumenthal R, Eloranta ML, Engel H, Alm G, Weiss S, et al. Interferon-beta is required for interferon-alpha production in mouse fibroblasts. Curr Biol 1998; 8:223-6.
79. Wheelock EF. Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin. Science 1965; 149:310-1.
81. Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW. Human immune interferon gene is located on chromosome 12. J Exp Med 1983; 157:1020-7.
82. Trent JM, Olson S, Lawn RM. Chromosomal localization of human leukocyte, fibroblast, and immune interferon genes by means of in situ hybridization. Proc Natl Acad Sci U S A 1982; 79:7809-13.
83. Derynck R, Leung DW, Gray PW, Goeddel DV. Human interferon gamma is encoded by a single class of mRNA. Nucleic Acids Res 1982; 10:3605-15.
84. Gray PW, Goeddel DV. Structure of the human immune interferon gene. Nature 1982; 298:859-63.
85. Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, et al. Three-dimensional structure of recombinant human interferon-gamma. Science 1991; 252:698-702.
86. Aguet M, Dembic Z, Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell 1988; 55:273-80.
87. Marsters SA, Pennica D, Bach E, Schreiber RD, Ashkenazi A. Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain. Proc Natl Acad Sci U S A 1995; 92:5401-5.
88. Gray PW, Leong S, Fennie EH, Farrar MA, Pingel JT, Fernandez-Luna J, et al. Cloning and expression of the cDNA for the murine interferon gamma receptor. Proc Natl Acad Sci U S A 1989; 86:8497-501.
89. Farlik M, Rapp B, Marie I, Levy DE, Jamieson AM, Decker T. Contribution of a TANK-binding kinase 1-interferon (IFN) regulatory factor 7 pathway to IFN-gamma-induced gene expression. Mol Cell Biol 2012; 32:1032-43.
90. Darnell JE, Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264:1415-21.
91. Mahboubi K, Pober JS. Activation of signal transducer and activator of transcription 1 (STAT1) is not sufficient for the induction of STAT1-dependent genes in endothelial cells. Comparison of interferon-gamma and oncostatin M. J Biol Chem 2002; 277:8012-21.
92. Rouyez MC, Lestingi M, Charon M, Fichelson S, Buzyn A, Dusanter-Fourt I. IFN regulatory factor-2 cooperates with STAT1 to regulate transporter associated with antigen processing-1 promoter activity. J Immunol 2005; 174:3948-58.
93. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005; 5:375-86.
94. Gade P, Ramachandran G, Maachani UB, Rizzo MA, Okada T, Prywes R, et al. An IFN-gamma-stimulated ATF6-C/EBP-beta-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc Natl Acad Sci U S A 2012; 109:10316-21.
95. Hu X, Ivashkiv LB. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 2009; 31:539-50.
96. Qiao Y, Giannopoulou EG, Chan CH, Park SH, Gong S, Chen J, et al. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 2013; 39:454-69.
97. Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 2007; 96:41-101.
98. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000; 100:655-69.
99. Oestreich KJ, Huang AC, Weinmann AS. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med 2011; 208:1001-13.
100. Teixeira LK, Fonseca BP, Vieira-de-Abreu A, Barboza BA, Robbs BK, Bozza PT, et al. IFN-gamma production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation. J Immunol 2005; 175:5931-9.
101. Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med 2009; 206:51-9.
102. Kannan Y, Yu J, Raices RM, Seshadri S, Wei M, Caligiuri MA, et al. IkappaBzeta augments IL-12- and IL-18-mediated IFN-gamma production in human NK cells. Blood 2011; 117:2855-63.
103. Zhu J, Jankovic D, Oler AJ, Wei G, Sharma S, Hu G, et al. The Transcription Factor T-bet Is Induced by Multiple Pathways and Prevents an Endogenous Th2 Cell Program during Th1 Cell Responses. Immunity 2012; 37:660-73.
104. Pham D, Vincentz JW, Firulli AB, Kaplan MH. Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function. J Immunol 2012; 189:832-40.
105. Allan RS, Zueva E, Cammas F, Schreiber HA, Masson V, Belz GT, et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 2012; 487:249-53.
106. Ogilvie RL, Sternjohn JR, Rattenbacher B, Vlasova IA, Williams DA, Hau HH, et al. Tristetraprolin mediates interferon-gamma mRNA decay. J Biol Chem 2009; 284:11216-23.
107. Ma F, Xu S, Liu X, Zhang Q, Xu X, Liu M, et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol 2011; 12:861-9.
108. Hovanessian AG. Interferon-induced and double-stranded RNA-activated enzymes: a specific protein kinase and 2',5'-oligoadenylate synthetases. J Interferon Res 1991; 11:199-205.
109. Patterson JB, Thomis DC, Hans SL, Samuel CE. Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. Virology 1995; 210:508-11.
110. Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 1990; 62:379-90.
111. Wenner CA, Guler ML, Macatonia SE, O'Garra A, Murphy KM. Roles of IFN-gamma and IFN-alpha in IL-12-induced T helper cell-1 development. J Immunol 1996; 156:1442-7.
112. Dick TP, Ruppert T, Groettrup M, Kloetzel PM, Kuehn L, Koszinowski UH, et al. Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands. Cell 1996; 86:253-62.
113. Wallach D, Fellous M, Revel M. Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells. Nature 1982; 299:833-6.
114. Figueiredo F, Koerner TJ, Adams DO. Molecular mechanisms regulating the expression of class II histocompatibility molecules on macrophages. Effects of inductive and suppressive signals on gene transcription. J Immunol 1989; 143:3781-6.
115. Chang CH, Flavell RA. Class II transactivator regulates the expression of multiple genes involved in antigen presentation. J Exp Med 1995; 181:765-7.
116. Lah TT, Hawley M, Rock KL, Goldberg AL. Gamma-interferon causes a selective induction of the lysosomal proteases, cathepsins B and L, in macrophages. FEBS Lett 1995; 363:85-9.
117. Xaus J, Cardo M, Valledor AF, Soler C, Lloberas J, Celada A. Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity 1999; 11:103-13.
118. Harvat BL, Seth P, Jetten AM. The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene 1997; 14:2111-22.
119. Matsuoka M, Nishimoto I, Asano S. Interferon-gamma impairs physiologic downregulation of cyclin-dependent kinase inhibitor, p27Kip1, during G1 phase progression in macrophages. Exp Hematol 1999; 27:203-9.
120. Kominsky S, Johnson HM, Bryan G, Tanabe T, Hobeika AC, Subramaniam PS, et al. IFNgamma inhibition of cell growth in glioblastomas correlates with increased levels of the cyclin dependent kinase inhibitor p21WAF1/CIP1. Oncogene 1998; 17:2973-9.
121. Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 1997; 17:5328-37.
122. Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 1995; 9:15-30.
123. Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J 1996; 15:3861-70.
124. Xu X, Fu XY, Plate J, Chong AS. IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res 1998; 58:2832-7.
125. Refaeli Y, Van Parijs L, Alexander SI, Abbas AK. Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med 2002; 196:999-1005.
126. Li X, McKinstry KK, Swain SL, Dalton DK. IFN-gamma acts directly on activated CD4+ T cells during mycobacterial infection to promote apoptosis by inducing components of the intracellular apoptosis machinery and by inducing extracellular proapoptotic signals. J Immunol 2007; 179:939-49.
127. Feng CG, Zheng L, Jankovic D, Bafica A, Cannons JL, Watford WT, et al. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol 2008; 9:1279-87.
128. Sarhan D, D'Arcy P, Wennerberg E, Liden M, Hu J, Winqvist O, et al. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-gamma. Eur J Immunol 2013; 43:249-57.
129. Schurch C, Riether C, Amrein MA, Ochsenbein AF. Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-gamma. J Exp Med 2013; 210:605-21.
130. de Kleijn S, Langereis JD, Leentjens J, Kox M, Netea MG, Koenderman L, et al. IFN-gamma-stimulated neutrophils suppress lymphocyte proliferation through expression of PD-L1. PLoS One 2013; 8:e72249.
131. Taub DD, Lloyd AR, Conlon K, Wang JM, Ortaldo JR, Harada A, et al. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 1993; 177:1809-14.
132. Rollins BJ, Yoshimura T, Leonard EJ, Pober JS. Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol 1990; 136:1229-33.
133. Taub DD, Conlon K, Lloyd AR, Oppenheim JJ, Kelvin DJ. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science 1993; 260:355-8.
134. Hou J, Baichwal V, Cao Z. Regulatory elements and transcription factors controlling basal and cytokine-induced expression of the gene encoding intercellular adhesion molecule 1. Proc Natl Acad Sci U S A 1994; 91:11641-5.
135. Jesse TL, LaChance R, Iademarco MF, Dean DC. Interferon regulatory factor-2 is a transcriptional activator in muscle where It regulates expression of vascular cell adhesion molecule-1. J Cell Biol 1998; 140:1265-76.
136. Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 2008; 159:1092-102.
137. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997; 15:323-50.
138. Cassatella MA, Bazzoni F, Flynn RM, Dusi S, Trinchieri G, Rossi F. Molecular basis of interferon-gamma and lipopolysaccharide enhancement of phagocyte respiratory burst capability. Studies on the gene expression of several NADPH oxidase components. J Biol Chem 1990; 265:20241-6.
139. Bosisio D, Polentarutti N, Sironi M, Bernasconi S, Miyake K, Webb GR, et al. Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide. Blood 2002; 99:3427-31.
140. Adib-Conquy M, Cavaillon JM. Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression. J Biol Chem 2002; 277:27927-34.
141. Hu X, Chung AY, Wu I, Foldi J, Chen J, Ji JD, et al. Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-gamma Pathways. Immunity 2008.
142. Pearl JE, Saunders B, Ehlers S, Orme IM, Cooper AM. Inflammation and lymphocyte activation during mycobacterial infection in the interferon-gamma-deficient mouse. Cell Immunol 2001; 211:43-50.
143. van den Broek MF, Muller U, Huang S, Zinkernagel RM, Aguet M. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev 1995; 148:5-18.
144. Buchmeier NA, Schreiber RD. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A 1985; 82:7404-8.
145. Kamijo R, Le J, Shapiro D, Havell EA, Huang S, Aguet M, et al. Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guerin and subsequent challenge with lipopolysaccharide. J Exp Med 1993; 178:1435-40.
146. Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 1988; 240:516-8.
147. Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, et al. SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 2011; 208:2055-67.
148. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 2011; 208:1189-201.
interferon gamma therapy for osteopetrosis. J Pediatr 1992; 121:119-24.151. Akhavan A, Rudikoff D. Atopic dermatitis: systemic immunosuppressive
therapy. Semin Cutan Med Surg 2008; 27:151-5.152. Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, et al. Open-
label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol Scand 2015; 132:7-15.
153. Wells M, Seyer L, Schadt K, Lynch DR. IFN-γ for Friedreich ataxia: present evidence. Neurodegener Dis Manag 2015; 5:497-504.
154. Fusiak T, Smaldone GC, Condos R. Pulmonary Fibrosis Treated with Inhaled Interferon-gamma (IFN-γ). J Aerosol Med Pulm Drug Deliv 2015; 28:406-10.
155. Diaz KT, Skaria S, Harris K, Solomita M, Lau S, Bauer K, et al. Delivery and safety of inhaled interferon-γ in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv 2012; 25:79-87.
156. Skaria SD, Yang J, Condos R, Smaldone GC. Inhaled Interferon and Diffusion Capacity in Idiopathic Pulmonary Fibrosis (IPF). Sarcoidosis Vasc Diffuse Lung Dis 2015; 32:37-42.
157. Reinisch W, de Villiers W, Bene L, Simon L, Rácz I, Katz S, et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010; 16:233-42.
158. Doffinger R, Helbert MR, Barcenas-Morales G, Yang K, Dupuis S, Ceron-Gutierrez L, et al. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin Infect Dis 2004; 38:e10-4.
159. Hoflich C, Sabat R, Rosseau S, Temmesfeld B, Slevogt H, Docke WD, et al. Naturally occurring anti-IFN-gamma autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans. Blood 2004; 103:673-5.
160. Kampmann B, Hemingway C, Stephens A, Davidson R, Goodsall A, Anderson S, et al. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest 2005; 115:2480-8.
161. Patel SY, Ding L, Brown MR, Lantz L, Gay T, Cohen S, et al. Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections. J Immunol 2005; 175:4769-76.
162. D'Ombrain MC, Robinson LJ, Stanisic DI, Taraika J, Bernard N, Michon P, et al. Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin Infect Dis 2008; 47:1380-7.
163. Halminen M, Simell O, Knip M, Ilonen J. Cytokine expression in unstimulated PBMC of children with type 1 diabetes and subjects positive for diabetes-associated autoantibodies. Scand J Immunol 2001; 53:510-3.
164. Haskins K, McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 1990; 249:1433-6.
165. Boissier MC, Chiocchia G, Bessis N, Hajnal J, Garotta G, Nicoletti F, et al. Biphasic effect of interferon-gamma in murine collagen-induced arthritis. Eur J Immunol 1995; 25:1184-90.
166. Chu CQ, Wittmer S, Dalton DK. Failure to suppress the expansion of the activated CD4 T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J Exp Med 2000; 192:123-8.
167. Chu CQ, Song Z, Mayton L, Wu B, Wooley PH. IFNgamma deficient C57BL/6 (H-2b) mice develop collagen induced arthritis with predominant usage of T cell receptor Vbeta6 and Vbeta8 in arthritic joints. Ann Rheum Dis 2003; 62:983-90.
168. Doodes PD, Cao Y, Hamel KM, Wang Y, Farkas B, Iwakura Y, et al. Development of proteoglycan-induced arthritis is independent of IL-17. J Immunol 2008; 181:329-37.
169. Patel SY, Doffinger R, Barcenas-Morales G, Kumararatne DS. Genetically determined susceptibility to mycobacterial infection. J Clin Pathol 2008; 61:1006-12.
170. Jouanguy E, Dupuis S, Pallier A, Doffinger R, Fondaneche MC, Fieschi C, et al. In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. J Clin Invest 2000; 105:1429-36.
171. Rosenzweig SD, Dorman SE, Uzel G, Shaw S, Scurlock A, Brown MR, et al. A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states. J Immunol 2004; 173:4000-8.
172. Vogt G, Chapgier A, Yang K, Chuzhanova N, Feinberg J, Fieschi C, et al. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 2005; 37:692-700.
173. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, Dorman SE, Fondaneche MC, Dupuis S, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999; 21:370-8.
174. Leung DY, Gao PS, Grigoryev DN, Rafaels NM, Streib JE, Howell MD, et al. Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-gamma response. J Allergy Clin Immunol 2011; 127:965-73 e1-5.
175. Gros E, Petzold S, Maintz L, Bieber T, Novak N. Reduced IFN-gamma receptor expression and attenuated IFN-gamma response by dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol 2011; 128:1015-21.
176. Akdis M, Trautmann A, Klunker S, Daigle I, Kucuksezer UC, Deglmann W, et al. T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J 2003; 17:1026-35.
177. Steinke JW, Liu L, Huyett P, Negri J, Payne SC, Borish L. Prominent role of IFN-gamma in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2013; 132:856-65 e1-3.
178. Pennino D, Bhavsar PK, Effner R, Avitabile S, Venn P, Quaranta M, et al. IL-22 suppresses IFN-gamma-mediated lung inflammation in asthmatic patients. J Allergy Clin Immunol 2013; 131:562-70.
179. Rebane A, Zimmermann M, Aab A, Baurecht H, Koreck A, Karelson M, et al. Mechanisms of IFN-gamma-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. J Allergy Clin Immunol 2012; 129:1297-306.
180. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994; 94:870-6.
181. Bieber T. Atopic dermatitis. Ann Dermatol 2010; 22:125-37.182. Trautmann A, Akdis M, Kleemann D, Altznauer F, Simon HU, Graeve T, et
al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000; 106:25-35.
183. Klunker S, Trautmann A, Akdis M, Verhagen J, Schmid-Grendelmeier P, Blaser K, et al. A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis. J Immunol 2003; 171:1078-84.
184. Basinski TM, Holzmann D, Eiwegger T, Zimmermann M, Klunker S, Meyer N, et al. Dual nature of T cell-epithelium interaction in chronic rhinosinusitis. J Allergy Clin Immunol 2009; 124:74-80 e1-8.
185. Coley WB. Practitioner. 1909; 83:589-613.186. Coley WB. Am J Med Sci 1893; 105:487-511.187. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An
endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975; 72:3666-70.
188. Kawakami M, Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med 1981; 154:631-9.
189. Mahoney JR, Jr., Beutler BA, Le Trang N, Vine W, Ikeda Y, Kawakami M, et al. Lipopolysaccharide-treated RAW 264.7 cells produce a mediator that inhibits lipoprotein lipase in 3T3-L1 cells. J Immunol 1985; 134:1673-5.
190. Beutler BA, Milsark IW, Cerami A. Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 1985; 135:3972-7.
191. Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 1985; 316:552-4.
192. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984; 312:724-9.
193. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature 1985; 313:803-6.
194. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, et al. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 1985; 228:149-54.
195. Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, et al. Molecular cloning and expression of human tumor
necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem 1985; 152:515-22.
196. Tang P, Hung MC, Klostergaard J. Human pro-tumor necrosis factor is a homotrimer. Biochemistry 1996; 35:8216-25.
197. Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 1988; 53:45-53.
198. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385:729-33.
199. Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 2003; 66:1403-8.
200. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ 2003; 10:45-65.
202. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137:1100-11.
203. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 2014; 343:1357-60.
204. Morioka S, Broglie P, Omori E, Ikeda Y, Takaesu G, Matsumoto K, et al. TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol 2014; 204:607-23.
205. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 2010; 16:452-9.
206. Hardyman MA, Wilkinson E, Martin E, Jayasekera NP, Blume C, Swindle EJ, et al. TNF-alpha-mediated bronchial barrier disruption and regulation by src-family kinase activation. J Allergy Clin Immunol 2013; 132:665-75 e8.
207. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697-708.
208. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60:1012-8.
209. Renzetti LM, Paciorek PM, Tannu SA, Rinaldi NC, Tocker JE, Wasserman MA, et al. Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways. J Pharmacol Exp Ther 1996; 278:847-53.
210. Cembrzynska-Nowak M, Szklarz E, Inglot AD, Teodorczyk-Injeyan JA. Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma. Am Rev Respir Dis 1993; 147:291-5.
211. Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 2005; 202:1213-23.
212. Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature 1990; 346:274-6.
213. Nakae S, Ho LH, Yu M, Monteforte R, Iikura M, Suto H, et al. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. J Allergy Clin Immunol 2007; 120:48-55.
214. Konno S, Gonokami Y, Kurokawa M, Kawazu K, Asano K, Okamoto K, et al. Cytokine concentrations in sputum of asthmatic patients. Int Arch Allergy Immunol 1996; 109:73-8.
215. Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI. Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 1992; 89:958-67.
216. Yoshida S, Hashimoto S, Nakayama T, Kobayashi T, Koizumi A, Horie T. Elevation of serum soluble tumour necrosis factor (TNF) receptor and IL-1 receptor antagonist levels in bronchial asthma. Clin Exp Immunol 1996; 106:73-8.
217. Watson ML, Smith D, Bourne AD, Thompson RC, Westwick J. Cytokines contribute to airway dysfunction in antigen-challenged guinea pigs: inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist. Am J Respir Cell Mol Biol 1993; 8:365-9.
218. Zuany-Amorim C, Haile S, Leduc D, Dumarey C, Huerre M, Vargaftig BB, et al. Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J Clin Invest 1995; 95:2644-51.
219. Lukacs NW, Strieter RM, Chensue SW, Widmer M, Kunkel SL. TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. J Immunol 1995; 154:5411-7.
220. Thomas PS, Yates DH, Barnes PJ. Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995; 152:76-80.
222. Chai OH, Han EH, Lee HK, Song CH. Mast cells play a key role in Th2 cytokine-dependent asthma model through production of adhesion molecules by liberation of TNF-alpha. Exp Mol Med 2011; 43:35-43.
223. Hessel EM, Van Oosterhout AJ, Van Ark I, Van Esch B, Hofman G, Van Loveren H, et al. Development of airway hyperresponsiveness is dependent on interferon-gamma and independent of eosinophil infiltration. Am J Respir Cell Mol Biol 1997; 16:325-34.
224. Rudmann DG, Moore MW, Tepper JS, Aldrich MC, Pfeiffer JW, Hogenesch H, et al. Modulation of allergic inflammation in mice deficient in TNF receptors. Am J Physiol Lung Cell Mol Physiol 2000; 279:L1047-57.
225. Kim HK, Lee CH, Kim JM, Ayush O, Im SY, Lee HK. Biphasic Late Airway Hyperresponsiveness in a Murine Model of Asthma. Int Arch Allergy Immunol 2012; 160:173-83.
226. Iwasaki M, Saito K, Takemura M, Sekikawa K, Fujii H, Yamada Y, et al. TNF-alpha contributes to the development of allergic rhinitis in mice. J Allergy Clin Immunol 2003; 112:134-40.
227. Mo JH, Kang EK, Quan SH, Rhee CS, Lee CH, Kim DY. Anti-tumor necrosis factor-alpha treatment reduces allergic responses in an allergic rhinitis mouse model. Allergy 2011; 66:279-86.
228. Sumimoto S, Kawai M, Kasajima Y, Hamamoto T. Increased plasma tumour necrosis factor-alpha concentration in atopic dermatitis. Arch Dis Child 1992; 67:277-9.
229. Junghans V, Gutgesell C, Jung T, Neumann C. Epidermal cytokines IL-1beta, TNF-alpha, and IL-12 in patients with atopic dermatitis: response to application of house dust mite antigens. J Invest Dermatol 1998; 111:1184-8.
230. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004; 113:651-7.
231. Botha T, Ryffel B. Reactivation of latent tuberculosis infection in TNF-deficient mice. J Immunol 2003; 171:3110-8.
232. Marino MW, Dunn A, Grail D, Inglese M, Noguchi Y, Richards E, et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A 1997; 94:8093-8.
233. Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993; 73:457-67.
234. Broide DH, Stachnick G, Castaneda D, Nayar J, Sriramarao P. Inhibition of eosinophilic inflammation in allergen-challenged TNF receptor p55/p75--and TNF receptor p55-deficient mice. Am J Respir Cell Mol Biol 2001; 24:304-11.
235. Cho JY, Pham A, Rosenthal P, Miller M, Doherty T, Broide DH. Chronic OVA allergen challenged TNF p55/p75 receptor deficient mice have reduced airway remodeling. Int Immunopharmacol 2011; 11:1038-44.
236. Kanehiro A, Lahn M, Makela MJ, Dakhama A, Fujita M, Joetham A, et al. Tumor necrosis factor-alpha negatively regulates airway hyperresponsiveness through gamma-delta T cells. Am J Respir Crit Care Med 2001; 164:2229-38.
237. Witte JS, Palmer LJ, O'Connor RD, Hopkins PJ, Hall JM. Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma. Eur J Hum Genet 2002; 10:82-5.
238. Minhas K, Micheal S, Ahmed F, Ahmed A. Strong association between the -308 TNF promoter polymorphism and allergic rhinitis in Pakistani patients. J Investig Allergol Clin Immunol 2010; 20:563-6.
239. Croft M, Benedict CA, Ware CF. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 2013; 12:147-68.
240. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen SE, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179:549-58.
241. Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008; 63:584-91.
242. Deveci F, Muz MH, Ilhan N, Kirkil G, Turgut T, Akpolat N. Evaluation of the anti-inflammatory effect of infliximab in a mouse model of acute asthma. Respirology 2008; 13:488-97.
243. Kim J, McKinley L, Natarajan S, Bolgos GL, Siddiqui J, Copeland S, et al. Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust. Clin Exp Allergy 2006; 36:122-32.
244. D'Haens G. Anti-TNF-alpha treatment strategies: results and clinical perspectives. Gastroenterol Clin Biol 2009; 33 Suppl 3:S209-16.
245. Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev 2015; 4:CD005468.
246. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001; 19:163-96.
247. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, et al. EULAR recommendations for the management of Behçet disease. Ann Rheum Dis 2008; 67:1656-62.
248. Tobin AM, Kirby B. TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs 2005; 19:47-57.
249. Wakefield LM, Hill CS. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat Rev Cancer 2013; 13:328-41.
250. Millan FA, Denhez F, Kondaiah P, Akhurst RJ. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development 1991; 111:131-43.
251. Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 1985; 316:701-5.
252. Marquardt H, Lioubin MN, Ikeda T. Complete amino acid sequence of human transforming growth factor type beta 2. J Biol Chem 1987; 262:12127-31.
253. ten Dijke P, Geurts van Kessel AH, Foulkes JG, Le Beau MM. Transforming growth factor type beta 3 maps to human chromosome 14, region q23-q24. Oncogene 1988; 3:721-4.
254. Hinck AP. Structural studies of the TGF-betas and their receptors - insights into evolution of the TGF-beta superfamily. FEBS Lett 2012; 586:1860-70.
255. Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, et al. Latent TGF-beta structure and activation. Nature 2011; 474:343-9.
256. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96:319-28.
257. Schultz-Cherry S, Lawler J, Murphy-Ullrich JE. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. J Biol Chem 1994; 269:26783-8.
258. Yehualaeshet T, O'Connor R, Green-Johnson J, Mai S, Silverstein R, Murphy-Ullrich JE, et al. Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999; 155:841-51.
259. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 1992; 71:1003-14.
260. Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin CH. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem 1994; 269:20172-8.
261. Groppe J, Hinck CS, Samavarchi-Tehrani P, Zubieta C, Schuermann JP, Taylor AB, et al. Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 2008; 29:157-68.
262. Radaev S, Zou Z, Huang T, Lafer EM, Hinck AP, Sun PD. Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily. J Biol Chem 2010; 285:14806-14.
263. Greenwald J, Fischer WH, Vale WW, Choe S. Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nat Struct Biol 1999; 6:18-22.
264. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature 1994; 370:341-7.
265. Liu X, Xiong C, Jia S, Zhang Y, Chen YG, Wang Q, et al. Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region. Nat Commun 2013; 4:1728.
266. Kashiwagi I, Morita R, Schichita T, Komai K, Saeki K, Matsumoto M, et al. Smad2 and Smad3 Inversely Regulate TGF-beta Autoinduction in Clostridium butyricum-Activated Dendritic Cells. Immunity 2015; 43:65-79.
267. Fang F, Shangguan AJ, Kelly K, Wei J, Gruner K, Ye B, et al. Early growth response 3 (Egr-3) is induced by transforming growth factor-beta and regulates fibrogenic responses. Am J Pathol 2013; 183:1197-208.
268. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113:685-700.
269. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425:577-84.
270. Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 2009; 19:71-88.
271. Mu E, Ding R, An X, Li X, Chen S, Ma X. Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and TGF-beta/Smad signaling pathway. Thromb Res 2012; 129:479-85.
272. Blahna MT, Hata A. Smad-mediated regulation of microRNA biosynthesis. FEBS Lett 2012; 586:1906-12.
273. Butz H, Racz K, Hunyady L, Patocs A. Crosstalk between TGF-beta signaling and the microRNA machinery. Trends Pharmacol Sci 2012; 33:382-93.
274. Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, et al. IL-35 Is a Novel Responsive Anti-inflammatory Cytokine — A New System of Categorizing Anti-inflammatory Cytokines. PLoS ONE 2012; 7:e33628.
275. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology 2006; 117:433-42.
277. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 2009; 15:757-65.
278. Wu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell 2009; 16:329-43.
279. Derynck R, Akhurst RJ. Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol 2007; 9:1000-4.
280. Salnikov AV, Roswall P, Sundberg C, Gardner H, Heldin NE, Rubin K. Inhibition of TGF-beta modulates macrophages and vessel maturation in
parallel to a lowering of interstitial fluid pressure in experimental carcinoma. Lab Invest 2005; 85:512-21.
281. Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol 2011; 179:1074-80.
282. Saitoh M, Miyazawa K. Transcriptional and post-transcriptional regulation in TGF-beta-mediated epithelial-mesenchymal transition. J Biochem 2012; 151:563-71.
283. Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-beta signaling in fibrosis. Growth Factors 2011; 29:196-202.
284. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312:117-21.
285. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003; 33:407-11.
286. Bernasconi P, Torchiana E, Confalonieri P, Brugnoni R, Barresi R, Mora M, et al. Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine. J Clin Invest 1995; 96:1137-44.
287. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16:585-601.
289. Wu CF, Chiang WC, Lai CF, Chang FC, Chen YT, Chou YH, et al. Transforming growth factor beta-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am J Pathol 2013; 182:118-31.
290. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001; 29:117-29.
291. Gomis RR, Alarcon C, He W, Wang Q, Seoane J, Lash A, et al. A FoxO-Smad synexpression group in human keratinocytes. Proc Natl Acad Sci U S A 2006; 103:12747-52.
292. Siegel PM, Shu W, Massague J. Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. J Biol Chem 2003; 278:35444-50.
293. Brenet F, Kermani P, Spektor R, Rafii S, Scandura JM. TGFbeta restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med 2013; 210:623-39.
294. Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. J Pathol 2011; 223:205-18.
295. Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 1993; 13:1155-62.
296. Yoshimura A, Muto G. TGF-beta function in immune suppression. Curr Top Microbiol Immunol 2011; 350:127-47.
297. Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von Boehmer H, et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 2006; 25:129-41.
298. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8:523-32.
299. Sugita K, Hanakawa S, Honda T, Kondoh G, Miyachi Y, Kabashima K, et al. Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios(+) regulatory T cells in vitro. Exp Dermatol 2015; 24:554-6.
300. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 2008; 9:194-202.
301. Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, et al. Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 2010; 185:842-55.
302. Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol 2013; 14:162-71.
303. Maruyama T, Li J, Vaque JP, Konkel JE, Wang W, Zhang B, et al. Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3. Nat Immunol 2011; 12:86-95.
304. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441:235-8.
305. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441:231-4.
306. Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity 2011; 34:396-408.
307. Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, et al. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 2009; 206:2407-16.
308. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 2010; 467:967-71.
309. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 2008; 9:1341-6.
310. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 2008; 9:1347-55.
311. Ramesh S, Wildey GM, Howe PH. Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim. Cell Cycle 2009; 8:11-7.
312. Borsutzky S, Cazac BB, Roes J, Guzman CA. TGF-beta receptor signaling is critical for mucosal IgA responses. J Immunol 2004; 173:3305-9.
313. Klinker MW, Lundy SK. Multiple mechanisms of immune suppression by B lymphocytes. Mol Med 2012; 18:123-37.
315. Jaksits S, Kriehuber E, Charbonnier AS, Rappersberger K, Stingl G, Maurer D. CD34+ cell-derived CD14+ precursor cells develop into Langerhans cells in a TGF-beta 1-dependent manner. J Immunol 1999; 163:4869-77.
316. Zhang Y, Zhang YY, Ogata M, Chen P, Harada A, Hashimoto S, et al. Transforming growth factor-beta1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway. Blood 1999; 93:1208-20.
317. Geissmann F, Revy P, Regnault A, Lepelletier Y, Dy M, Brousse N, et al. TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 1999; 162:4567-75.
318. Mohammed J, Gunderson AJ, Khong HH, Koubek RD, Udey MC, Glick AB. TGFbeta1 overexpression by keratinocytes alters skin dendritic cell homeostasis and enhances contact hypersensitivity. J Invest Dermatol 2013; 133:135-43.
319. Yamaguchi M, Yu L, Hishikawa Y, Yamanoi A, Kubota H, Nagasue N. Growth kinetic study of human hepatocellular carcinoma using proliferating cell nuclear antigen and Lewis Y antigen: their correlation with transforming growth factor-alpha and beta 1. Oncology 1997; 54:245-51.
320. Sato K, Kawasaki H, Nagayama H, Enomoto M, Morimoto C, Tadokoro K, et al. TGF-beta 1 reciprocally controls chemotaxis of human peripheral blood monocyte-derived dendritic cells via chemokine receptors. J Immunol 2000; 164:2285-95.
322. Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol 2005; 6:600-7.
323. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23:549-55.
324. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 2009; 16:183-94.
325. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359:693-9.
326. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 1993; 90:770-4.
327. Aoki CA, Borchers AT, Li M, Flavell RA, Bowlus CL, Ansari AA, et al. Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmun Rev 2005; 4:450-9.
328. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 2009; 9:447-53.
329. Miyara M, Wing K, Sakaguchi S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. J Allergy Clin Immunol 2009; 123:749-55; quiz 56-7.
330. Rosenblum MD, Gratz IK, Paw JS, Abbas AK. Treating human autoimmunity: current practice and future prospects. Sci Transl Med 2012; 4:125sr1.
331. Caraci F, Spampinato S, Sortino MA, Bosco P, Battaglia G, Bruno V, et al. Dysfunction of TGF-beta1 signaling in Alzheimer's disease: perspectives for neuroprotection. Cell Tissue Res 2012; 347:291-301.
332. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, et al. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001; 7:612-8.
333. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 2008; 1782:197-228.
334. Pardali E, Goumans MJ, ten Dijke P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 2010; 20:556-67.
335. Cai J, Pardali E, Sanchez-Duffhues G, ten Dijke P. BMP signaling in vascular diseases. FEBS Lett 2012; 586:1993-2002.
336. Grainger DJ. TGF-beta and atherosclerosis in man. Cardiovasc Res 2007; 74:213-22.
337. Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res 2009; 19:116-27.
338. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007; 13:952-61.
339. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Trozzi L, Candelaresi C, et al. Semaphorin 7A contributes to TGF-beta-mediated liver fibrogenesis. Am J Pathol 2013; 183:820-30.
340. Yu M, Trobridge P, Wang Y, Kanngurn S, Morris SM, Knoblaugh S, et al. Inactivation of TGF-beta signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene 2014; 33:1538-47.
341. de Miranda NF, van Dinther M, van den Akker BE, van Wezel T, ten Dijke P, Morreau H. Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2. Gastroenterology 2015; 148:1427-37 e8.
342. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303:848-51.
343. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119:1420-8.
344. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133:704-15.
345. Stadler SC, Vincent CT, Fedorov VD, Patsialou A, Cherrington BD, Wakshlag JJ, et al. Dysregulation of PAD4-mediated citrullination of nuclear GSK3beta activates TGF-beta signaling and induces epithelial-to-
mesenchymal transition in breast cancer cells. Proc Natl Acad Sci U S A 2013; 110:11851-6.
346. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, et al. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 2007; 117:1305-13.
347. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 2009; 11:1287-96.
348. Chu CY, Sheen YS, Cha ST, Hu YF, Tan CT, Chiu HC, et al. Induction of chemokine receptor CXCR4 expression by transforming growth factor-beta1 in human basal cell carcinoma cells. J Dermatol Sci 2013; 72:123-33.
349. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001; 7:1118-22.
350. Arteaga CL, Dugger TC, Winnier AR, Forbes JT. Evidence for a positive role of transforming growth factor-beta in human breast cancer cell tumorigenesis. J Cell Biochem Suppl 1993; 17G:187-93.
351. Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 2009; 69:7775-83.
352. Ohno I, Nitta Y, Yamauchi K, Hoshi H, Honma M, Woolley K, et al. Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation. Am J Respir Cell Mol Biol 1996; 15:404-9.
353. Minshall EM, Leung DY, Martin RJ, Song YL, Cameron L, Ernst P, et al. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1997; 17:326-33.
354. Vignola AM, Chanez P, Chiappara G, Merendino A, Zinnanti E, Bousquet J, et al. Release of transforming growth factor-beta (TGF-beta) and fibronectin by alveolar macrophages in airway diseases. Clin Exp Immunol 1996; 106:114-9.
355. Torrego A, Hew M, Oates T, Sukkar M, Fan Chung K. Expression and activation of TGF-beta isoforms in acute allergen-induced remodelling in asthma. Thorax 2007; 62:307-13.
356. Bottoms SE, Howell JE, Reinhardt AK, Evans IC, McAnulty RJ. Tgf-Beta isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One 2010; 5:e9674.
357. Pulleyn LJ, Newton R, Adcock IM, Barnes PJ. TGFbeta1 allele association with asthma severity. Hum Genet 2001; 109:623-7.
358. Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, et al. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med 2004; 169:214-9.
359. Ueda T, Niimi A, Matsumoto H, Takemura M, Yamaguchi M, Matsuoka H, et al. TGFB1 promoter polymorphism C-509T and pathophysiology of asthma. J Allergy Clin Immunol 2008; 121:659-64.
360. Ierodiakonou D, Postma DS, Koppelman GH, Gerritsen J, ten Hacken NH, Timens W, et al. TGF-beta1 polymorphisms and asthma severity, airway inflammation, and remodeling. J Allergy Clin Immunol 2013; 131:582-5.
361. Haneda K, Sano K, Tamura G, Sato T, Habu S, Shirato K. TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia. J Immunol 1997; 159:4484-90.
362. Hansen G, McIntire JJ, Yeung VP, Berry G, Thorbecke GJ, Chen L, et al. CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 2000; 105:61-70.
363. Joetham A, Takeda K, Taube C, Miyahara N, Matsubara S, Koya T, et al. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J Immunol 2007; 178:1433-42.
364. Scherf W, Burdach S, Hansen G. Reduced expression of transforming growth factor beta 1 exacerbates pathology in an experimental asthma model. Eur J Immunol 2005; 35:198-206.
365. Schramm C, Herz U, Podlech J, Protschka M, Finotto S, Reddehase MJ, et al. TGF-beta regulates airway responses via T cells. J Immunol 2003; 170:1313-9.
366. Chen W, Wahl SM. TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003; 14:85-9.
367. Ray A, Khare A, Krishnamoorthy N, Qi Z, Ray P. Regulatory T cells in many flavors control asthma. Mucosal Immunol 2010; 3:216-29.
368. Thorburn AN, Hansbro PM. Harnessing regulatory T cells to suppress asthma: from potential to therapy. Am J Respir Cell Mol Biol 2010; 43:511-9.
369. Presser K, Schwinge D, Wegmann M, Huber S, Schmitt S, Quaas A, et al. Coexpression of TGF-beta1 and IL-10 enables regulatory T cells to completely suppress airway hyperreactivity. J Immunol 2008; 181:7751-8.
370. Worthington JJ, Kelly A, Smedley C, Bauche D, Campbell S, Marie JC, et al. Integrin alphavbeta8-Mediated TGF-beta Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation. Immunity 2015; 42:903-15.
371. Tu E, Chia PZ, Chen W. TGFbeta in T cell biology and tumor immunity: Angel or devil? Cytokine Growth Factor Rev 2014; 25:423-35.
372. Kenyon NJ, Ward RW, McGrew G, Last JA. TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice. Thorax 2003; 58:772-7.
373. McMillan SJ, Xanthou G, Lloyd CM. Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway. J Immunol 2005; 174:5774-80.
374. Le AV, Cho JY, Miller M, McElwain S, Golgotiu K, Broide DH. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. J Immunol 2007; 178:7310-6.
375. Alcorn JF, Rinaldi LM, Jaffe EF, van Loon M, Bates JH, Janssen-Heininger YM, et al. Transforming growth factor-beta1 suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med 2007; 176:974-82.
376. Fattouh R, Midence NG, Arias K, Johnson JR, Walker TD, Goncharova S, et al. Transforming growth factor-beta regulates house dust mite-induced allergic airway inflammation but not airway remodeling. Am J Respir Crit Care Med 2008; 177:593-603.
377. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003; 112:1029-36.
378. Cho JY, Miller M, Baek KJ, Han JW, Nayar J, Lee SY, et al. Inhibition of airway remodeling in IL-5-deficient mice. J Clin Invest 2004; 113:551-60.
379. Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 2003; 111:1293-8.
380. Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q. Role of transforming growth factor-beta in airway remodeling in asthma. Am J Respir Cell Mol Biol 2011; 44:127-33.
381. Dehzad N, Bopp T, Reuter S, Klein M, Martin H, Ulges A, et al. Regulatory T cells more effectively suppress Th1-induced airway inflammation compared with Th2. J Immunol 2011; 186:2238-44.
382. Sugita K, Kabashima K, Sawada Y, Haruyama S, Yoshioka M, Mori T, et al. Blocking of CTLA-4 on lymphocytes improves the sensitivity of lymphocyte transformation tests in a patient with nickel allergy. Eur J Dermatol 2012; 22:268-9.
383. Soyer OU, Akdis M, Ring J, Behrendt H, Crameri R, Lauener R, et al. Mechanisms of peripheral tolerance to allergens. Allergy 2013; 68:161-70.
384. Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, et al. Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy 2003; 33:1717-24.
385. Arkwright PD, Chase JM, Babbage S, Pravica V, David TJ, Hutchinson IV. Atopic dermatitis is associated with a low-producer transforming growth factor beta(1) cytokine genotype. J Allergy Clin Immunol 2001; 108:281-4.
386. Anthoni M, Wang G, Deng C, Wolff HJ, Lauerma AI, Alenius HT. Smad3 signal transducer regulates skin inflammation and specific IgE response in murine model of atopic dermatitis. J Invest Dermatol 2007; 127:1923-9.
388. Toda M, Leung DY, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol 2003; 111:875-81.
389. Verhagen J, Blaser K, Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy: T-regulatory cells and more. Immunol Allergy Clin North Am 2006; 26:207-31, vi.
390. Schnopp C, Rad R, Weidinger A, Weidinger S, Ring J, Eberlein B, et al. Fox-P3-positive regulatory T cells are present in the skin of generalized atopic eczema patients and are not particularly affected by medium-dose UVA1 therapy. Photodermatol Photoimmunol Photomed 2007; 23:81-5.
391. Caproni M, Torchia D, Antiga E, Volpi W, del Bianco E, Fabbri P. The effects of tacrolimus ointment on regulatory T lymphocytes in atopic dermatitis. J Clin Immunol 2006; 26:370-5.
392. Ou LS, Goleva E, Hall C, Leung DY. T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 2004; 113:756-63.
393. Ito T, Aoshima M, Ito N, Uchiyama I, Sakamoto K, Kawamura T, et al. Combination therapy with oral PUVA and corticosteroid for recalcitrant alopecia areata. Arch Dermatol Res 2009; 301:373-80.
394. Brandt C, Pavlovic V, Radbruch A, Worm M, Baumgrass R. Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Allergy 2009; 64:1588-96.
395. Salib RJ. Transforming growth factor-beta gene expression studies in nasal mucosal biopsies in naturally occurring allergic rhinitis. Ann R Coll Surg Engl 2007; 89:563-73.
396. Kim SH, Yang EM, Lee HN, Cho BY, Ye YM, Park HS. Combined effect of IL-10 and TGF-beta1 promoter polymorphisms as a risk factor for aspirin-intolerant asthma and rhinosinusitis. Allergy 2009; 64:1221-5.
397. Ciprandi G, De Amici M, Tosca M, Marseglia G. Serum transforming growth factor-beta levels depend on allergen exposure in allergic rhinitis. Int Arch Allergy Immunol 2010; 152:66-70.
398. Ouyang Y, Nakao A, Han D, Zhang L. Transforming growth factor-beta1 promotes nasal mucosal mast cell chemotaxis in murine experimental allergic rhinitis. ORL J Otorhinolaryngol Relat Spec 2012; 74:117-23.
399. Yang YC, Zhang N, Van Crombruggen K, Hu GH, Hong SL, Bachert C. Transforming growth factor-beta1 in inflammatory airway disease: a key for understanding inflammation and remodeling. Allergy 2012; 67:1193-202.
401. Kim JS, Sampson HA. Food allergy: a glimpse into the inner workings of gut immunology. Curr Opin Gastroenterol 2012; 28:99-103.
402. Liu ZQ, Wu Y, Song JP, Liu X, Liu Z, Zheng PY, et al. Tolerogenic CX3CR1+ B cells suppress food allergy-induced intestinal inflammation in mice. Allergy 2013; 68:1241-8.
403. Okamoto A, Kawamura T, Kanbe K, Kanamaru Y, Ogawa H, Okumura K, et al. Suppression of serum IgE response and systemic anaphylaxis in a food allergy model by orally administered high-dose TGF-beta. Int Immunol 2005; 17:705-12.
404. Ando T, Hatsushika K, Wako M, Ohba T, Koyama K, Ohnuma Y, et al. Orally administered TGF-beta is biologically active in the intestinal mucosa and enhances oral tolerance. J Allergy Clin Immunol 2007; 120:916-23.
405. Penttila IA. Milk-derived transforming growth factor-beta and the infant immune response. J Pediatr 2010; 156:S21-5.
406. Diebold RJ, Eis MJ, Yin M, Ormsby I, Boivin GP, Darrow BJ, et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci U S A 1995; 92:12215-9.
407. Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006; 25:441-54.
408. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998; 93:1159-70.
409. Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, et al. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997; 124:2659-70.
410. Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN, et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 1995; 11:409-14.
411. Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 1995; 11:415-21.
412. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 2013; 19:704-12.
413. Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 2000; 26:19-20.
414. Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem 2003; 278:7718-24.
415. Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 2012; 44:922-7.
416. Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 2012; 44:916-21.
417. Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, Chichester K, Myers L, Halushka MK, et al. TGFbeta receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med 2013; 5:195ra94.
418. Rampazzo A, Beffagna G, Nava A, Occhi G, Bauce B, Noiato M, et al. Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes. Eur J Hum Genet 2003; 11:69-76.
419. Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, et al. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 2005; 65:366-73.
420. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005; 37:275-81.
421. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268:1336-8.
422. Anscher MS, Thrasher B, Zgonjanin L, Rabbani ZN, Corbley MJ, Fu K, et al. Small molecular inhibitor of transforming growth factor-beta protects against
development of radiation-induced lung injury. Int J Radiat Oncol Biol Phys 2008; 71:829-37.
423. Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, et al. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 2007; 13:204-10.
424. Watanabe Y, Kinoshita A, Yamada T, Ohta T, Kishino T, Matsumoto N, et al. A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-beta1 (TGF-beta1) and its signaling pathway. J Hum Genet 2002; 47:478-83.