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Current reviews of allergy and clinical immunology(Supported by
an unrestricted educational grant from Novartis Pharmaceuticals
Corporation)
Series editor: Harold S. Nelson, MD
Signal transducer and activator of transcriptionsignals in
allergic disease
Weiguo Chen, PhD, and Gurjit K. Khurana Hershey, MD, PhD
Cincinnati, Ohio
This activity is available for CME credit. See page 42A for
important information.
Signal transducer and activator of transcription (STAT)
proteins are a group of transcription factors that transmit
signals from the extracellular milieu of cells to the
nucleus.
They are crucial for the signaling of many cytokines that
are
mediators of allergic inflammation and impact various cell
types critical to allergy including epithelial cells, mast
cells,
lymphocytes, dendritic cells, and eosinophils. Dysregulation
of
STAT signaling has been implicated in allergic disease,
highlighting the importance of these ubiquitous molecules in
allergic inflammation and the potential of these pathways as
a
target for therapeutic intervention. This review will
summarize
the current understanding of the roles of STAT signaling in
allergic disease and the potential of targeting STATs for
the
treatment of allergic disorders, emphasizing recent
observations. (J Allergy Clin Immunol 2007;119:529-41.)
Key words: Allergy, STAT, cytokine, JAK-STAT, review
During allergic inflammation, preformed and newlysynthesized
cytokines are released that contribute to thepathology seen in
allergic diseases. These cytokines havea wide range of activities
on different cell types. Theyexert their effects by binding to
specific cell surfacereceptors and inducing the expression of
relevant targetgenes. The discovery of signal transducer and
activator oftranscription (STAT) proteins over 15 years ago
provideda key molecular link between the binding of a cytokine
toits cell surface receptor and the induction of specific
genes.This link between the interferon (IFN) receptor and
genetranscription in the first report of a STAT protein
resulted
From the Division of Allergy and Immunology, Cincinnati
Children’s Hospital
Medical Center, and the Department of Pediatrics, University of
Cincinnati.
Disclosure of potential conflict of interest: The authors have
declared that they
have no conflict of interest.
Received for publication December 14, 2006; revised January 3,
2007;
accepted for publication January 5, 2007.
Reprint requests: Gurjit K. Khurana Hershey, MD, PhD, Division
of Allergy and
Immunology, Cincinnati Children’s Hospital Medical Center, 3333
Burnet
Avenue, MLC 7028, Cincinnati, OH 45229. E-mail:
Gurjit.Hershey@
cchmc.org.
0091-6749/$32.00
� 2007 American Academy of Allergy, Asthma &
Immunologydoi:10.1016/j.jaci.2007.01.004
in the discovery of the Janus kinase (JAK)-STAT path-way.1 Many
interleukins and members of the hematopoi-etin family utilize this
pathway to transduce their signals.These distinct factors transmit
their signals via 4 JAK and7 STAT molecules. JAKs constitutively
associated withthe receptors via conserved box-1 motifs are
broughtinto proximity following ligand-receptor interactionsleading
to transphosphorylation and resultant activationof JAKs. Activated
JAKs then phosphorylate specific ty-rosine residues in the
cytoplasmic region of the receptorthat can serve as docking sites
for STAT monomers.STAT monomers associate with the phosphorylated
tyro-sine sites and become tyrosine phosphorylated through
theaction of JAKs. Activated STATs are released from the re-ceptor,
dimerize, translocate to the nucleus, bind specificcanonical DNA
elements, and initiate cytokine-specificgene transcription. The
preferred binding sites for STATtranscription factors consist of
the palindromic motifTTC(Xn)GAA, where the number of nucleotides
separat-ing the half-sites can be from 2 to 4 nucleotides. The
JAK/STAT pathway is central to many fundamental biologicprocesses
and is tightly regulated by several mechanismsalong the signaling
cascade, including suppressor of cyto-kine signaling and protein
inhibitor of activated STAT, assummarized in Fig 1.2 JAK/STAT
dysregulation has beenbeen implicated in many disease processes,
including al-lergic inflammation. This review will summarize the
roleof STATs in allergic inflammation.
Abbreviations usedCRM: Chromosome region
maintenance/exportin
FOXP3: Forkhead box P3
JAK: Janus kinase
LMB: Leptomycin B
NES: Nuclear export signal
SH: SRC homology
SLIM: STAT-interacting LIM protein
SNP: Single nucleotide polymorphism
STAT: Signal transducer and activator of transcription
Treg: Regulatory T cell
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mailto:[email protected]:[email protected]
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FIG 1. Overview of STAT signaling pathway and regulation.
OVERVIEW OF STAT PROTEINS
Structure
The STAT protein family has 7 members: STAT1through STAT6,
including STAT5A and STAT5B.Recently, a STAT6 homologue (STAT6B),
which maybe generated by alternative splicing, was identified.3
STATs are activated in response to distinct stimuli and in-duce
the transcription of genes that can elicit diverse bio-logical
outcomes. STAT homologs have been identified insimple eukaryotes,
suggesting that they arose from a sin-gle gene.4 All STAT proteins
share the same overall
structure (Fig 2), including an N-terminal domain, acoiled-coil
domain, a DNA-binding domain, a linkerdomain, an SRC homology 2
(SH2) domain, a conservedsingle tyrosine residue that is
phosphorylated followingactivation, and a carboxy terminal that
facilitates tran-scriptional activation.2 STATs are activated by
tyrosinephosphorylation of the conserved tyrosine residue in
thetransactivation domain, and this modification serves as
amolecular switch that alters their conformation, enablingtheir
dimer formation through reciprocal tyrosine phos-phorylation and
SH2-domain interactions and specificbinding to DNA. Although some
STAT molecules form
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FIG 2. Structure of STAT proteins. a.a., Amino acid; NTD,
amino-terminal domain; DBD, DNA-binding domain;
TAD, transactivation domain.
TABLE I. Functions of STAT proteins
Gene
Phenotype
of knockout mice Human deficiency
Dysregulation
in human diseases References
STAT1 Impaired IFN signaling Mycobacterial and viral
diseases
IBD, rheumatoid arthritis, celiac
disease, Alzheimer disease,
multiple sclerosis, ischemic
heart disease, cancers
10, 11, 22, 24-31
STAT2 Impaired IFN signaling IBD, carcinoid tumor 12, 31, 32
STAT3 Embryonic lethal, impaired
IL-2, IL-6, and IL-10 signaling
IBD, psoriasis, multiple
sclerosis, cancers
13, 25, 30, 33, 34
STAT4 Impaired IL-12 signaling COPD, rheumatoid arthritis,
psoriasis, Sezary syndrome
14, 29, 35-37
STAT5A Impaired PRL signaling IBD, cancers, diabetes,
ischemic heart disease
15-18, 23, 27, 30,
38-40
STAT5B Impaired GH signaling GH insensitivity with
immunodeficiency
STAT6 Impaired IL-4 and IL-13
signaling
Asthma, atopic allergic rhinitis,
ischemic heart disease,
Hodgkin lymphoma
19-21, 29, 41-44
IBD, Inflammatory bowel disease; COPD, chronic obstructive
pulmonary disease; PRL, prolactin; GH, growth hormone.
homodimers or homotetramers with each other in an
un-phosphorylated state, it is the specific conformation
oftyrosine-phosphorylated dimers that enables STATs tobind to
consensus sequences in target genes.5-9 The diversefunctions of
STATs have been elucidated by studies inmouse gene targeting
models,10-21 human deficiency,22,23 andassociated human diseases
for STAT1,24-31 STAT2,31,32
STAT3,25,30,33,34 STAT4,29,35-37 STAT5,27,30,38-40
andSTAT629,41-44 (Table I).
STAT Phosphorylation
Tyrosine phosphorylation of STATs is initiated predom-inantly by
cytokine binding to cell-surface cytokine recep-tors. The
intracellular domains of many cytokine receptorsare constitutively
associated with JAK tyrosine kinases via
conserved box-1 motifs. There are 4 mammalian JAK
kinases (JAK1, JAK2, JAK3, and Tyk2), which each consist
of 7 conserved JAK homology (JH) domains. JAKs have both
a pseudokinase domain (JH1) and a true catalytic kinase
(JH2), leading to their being named after the mythologic
Roman god Janus who had 2 faces. The other domains,
JH3-JH7, mediate associaton with receptors.45 The JAK-
STAT pathway is critical for the response to cytokines crit-
ical for allergic inflammation, including IL-4 and
IL-13.Alternative activation pathways exist for STAT activa-
tion. JAKs can be activated in response to distinct ligands
that bind to G-protein coupled 7-transmembrane recep-tors.
Prostaglandins have been reported to activate STATs.Prostaglandin
E2 interacts with its nuclear receptor EP1,a G-protein-coupled
receptor, to activate STAT3 in
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nucleus.46 The G-protein coupled receptor-mediatedSTAT3
activation requires protein kinase A (PKA),c-Jun N-terminal kinase
(JNK), and PI3 kinase (PI3K).47
Angiotensin II and some chemokines, such as CC-chemo-kine ligand
5 (CCL5; also known as RANTES) signal viaG-protein coupled
receptors and activate STATs in aJak-dependent manner.48-51 STAT3
and STAT5 can alsobe activated by non-receptor oncogenic tyrosine
kinasesthat are of viral origin or are generated by
chromosomaltranslocation, such as v-Src and breakpoint
clusterregion-Abelson, respectively.52 The activity of STAT3and
STAT5 is dysregulated in a variety of human tumors.STAT3 and STAT5
acquire oncogenic potential throughconstitutive tyrosine
phosphorylation, and this activityhas been shown to be required to
sustain a transformedphenotype. Disruption of STAT3 and STAT5
signaling intransformed cells therefore represents an excellent
oppor-tunity for targeted cancer therapy. In contrast to STAT3and
STAT5, STAT1 negatively regulates cell proliferationand
angiogenesis and thereby inhibits tumor formation.STAT1 and its
downstream targets have been shown tobe reduced in a variety of
human tumors, and this pathwayis another potential target for
cancer therapy.53
In some STATs, the C-terminal region also contains aserine
residue that is phosphorylated, and this phospho-rylation has been
found to regulate the transcriptionalactivity of STATs.54 Serine
phosphorylation was firstreported for STAT1 and STAT3 and mapped to
Ser727.55-58 STAT1 and STAT3 serine phosphorylation isrequired for
maximal transcriptional activity,59 and serinephosphorylation of
STAT C-termini may contribute tothe specificity of signaling.60
Serine phosphorylation ofSTAT1 is independent of the tyrosine
phosphorylation, al-though serine kinases may recognize
tyrosine-phosphory-lated STAT1 preferentially in response to
IFN-g.61
STAT cofactors
Various cytokines and growth factors use overlappingJAKs and
STATs to induce their diverse and distinctfunctions. One mechanism
by which transcription factorsmediate specificity for the promoters
they activate is viainteraction with specific cofactors. Cofactors
of DNA-binding transcriptional activators are essential for
achiev-ing the threshold level of gene activation required
toovercome baseline repressive effects of nucleosomes andother
chromatin constituents. The coregulatory mecha-nisms by which STATs
assemble transcriptional machin-ery and selectively regulate
specific gene expression arenot clear, but coactivators have been
shown to be impor-tant for STAT activation. The activation of
STAT1requires a DNA replication factor, eukaryotic minichro-mosome
maintenance 5 (MCM5).62 The activation ofSTAT3 involves
CREB-binding protein (CBP)/p300through acetylation. STAT3 is
acetylated at a lysine resi-due in the C-terminal transactivation
domain by CBP/p300 and activated for its DNA-binding ability and
tran-scriptional activity.63,64 A transcriptional cofactor
forSTAT6, collaborator of STAT6 (CoaSt6), was recentlydescribed.65
CoaSt6 interacts with STAT6 in vivo and
amplifies IL-4-induced STAT6-dependent gene expres-sion. Aside
from the STATs that are activated via theJAK-STAT pathway,
additional transcription factors andcofactors that are activated
lead to activation of specificgenes via direct and indirect
interactions with STATs.66
STAT nuclear import and export
Nuclear translocation is crucial for the function ofSTATs. The
movement of large molecules between thecytoplasm and nucleus is
restricted and is a potential targetfor transcriptional regulation
by controlling the accessof transcription factors to the nucleus.
Because STATactivation is critical to many pathways involved in
thedevelopment of allergy and allergic inflammation, regu-lation of
STAT nuclear trafficking is a potential target fortherapeutic
intervention.
Nuclear localization occurs both at the level of nuclearimport
and nuclear export.67 STATs are translocated intonucleus in
response to cytokine stimulation to activategene expression and
subsequently exported back to thecytoplasm. Thus, nuclear import
and export are importantpotential regulatory points. Although the
STAT proteinsshare similar structural features, their respective
nuclear-cytoplasmic localization is distinctly regulated. The
recog-nition signals are amino-acid sequences that function
eitheras nuclear-localization signals (NLSs) or
nuclear-exportsignals (NESs). These signals can function
constitutivelyor conditionally depending on protein
modifications(that is, phosphorylation) or association with another
pro-tein that can alter the conformation of the protein.
Thus,association with different proteins can result in
differentlocalization patterns. STAT1 can form a complex
withtyrosine-phosphorylated STAT2 and a non-STAT
factor,IFN-regulatory factor 9 (IRF9).68 This complex,
ISGF3,translocates from the cytoplasm to the nucleus and
spe-cifically binds to the IFN-stimulated response element(ISRE) in
the promoters of responsive genes. STAT2dimerizes with STAT1 after
tyrosine phosphorylationand accumulates in the nucleus only in the
presence ofSTAT1.69 STAT2 does not form phosphorylated homo-dimers.
STAT1 is also tyrosine phosphorylated in re-sponse to IFN-g and
forms a homodimer that binds to adistinct DNA target known as the
IFN-g–activated site(GAS). Importin-a5 recognizes
tyrosine-phosphorylatedSTAT1 either in the form of IFN-stimulated
gene factor3 (ISGF3) or as a homodimer.70 A single leucine
residueat position 407 is required for binding to importin-a5and
transport into the nucleus.70 Interestingly, the bindingsite on
importin-a for the phosphorylated STAT1 dimeris distinct from
conventional NLS-containing proteins.52
It has been hypothesized that this would enable a STAT1dimer to
bind to importin-a5 that is already occupied withcargo and ensure
that STAT1 dimers are readily movedto the nucleus independent of
rate-limiting quantitiesof importin-a5. STAT2 does not form
phosphorylated ho-modimers; nuclear import depends on
heterodimerizationwith STAT1.68,69,71-73
Maintenance of STAT6 activity requires ongoing JAKkinase
activity and a continuous cycle of activation,
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deactivation, nuclear export, and reactivation.74
Similarly,nuclear accumulation of STAT1 is transient, and
withinhours, the STAT1 protein recycles back to the cyto-plasm.75
STAT5 also undergoes nucleocytoplasmiccycles upon erythropoietin
(EPO) stimulation.76 Thenuclear export is often mediated by the
leucine-rich nu-clear export signals (NESs) that consist of short
sequencesof hydrophobic amino acids with the consensus of
LX(1-3)LX(2-3)LXL.
59,77 The NES interacts with chromosomeregion
maintenance/exportin 1 (CRM1),78,79 and the in-teraction can be
disrupted by antibiotic leptomycin B(LMB).80,81 Both LMB-sensitive
and LMB-insensitivenuclear export exists for STAT1 and STAT4.82,83
Thus,non–LMB-sensitive nuclear export pathways for STATsexist, but
have not been well defined.
Several NES elements of STAT1 have been re-ported.82,84-86 A
conserved leucine-rich NES (amino acids302-314) in the coiled-coil
domain of STAT1 is requiredfor STAT1 nuclear export after IFN-g
treatment.82 A func-tional NES of STAT1 is located in the
DNA-bindingdomain of STAT1 (amino acids 392-413).
Interestingly,this region includes the Leu407, which is required
fornuclear import of STAT1. Thus, the nuclear import andexport
sequences are overlapping and may be counter-regulatory based on
the conformation of this region.Dephosphorylation of STAT1 and
dissociation fromDNA results in the recognition of NES by CRM1 and
nu-clear export of STAT1.85 A leucine-rich NES (amino acids400-410)
in the STAT1 DNA-binding domain containsLMB-sensitive nuclear
export activity. This NES is notimportant for the nuclear export of
unphosphorylatedSTAT1, but it is involved in the nuclear export of
tyro-sine-phosphorylated STAT1.86 The nucleocytoplasmicshuttling of
unphosphorylated STAT1 is controlled by nu-cleoporins, Nup153 and
Nup214, and CRM1-dependentnuclear export.87
Three NES elements were identified in STAT3 (aminoacids 306-318,
404-414, and 524-535).88 The first 2 NEScorrespond to the NES in
STAT1, whereas the third isnovel in STAT3. The NES 306-318 is
involved in nuclearexport in stimulated cells, whereas NES 404-414
and524-535 are involved in basal nuclear export. The NES201-210,
which has been shown possessing nuclear exportactivity for STAT1,
does not have any nuclear export ac-tivity for STAT3.88
Constitutive nucleocytoplasmic shut-tling is present for STAT3 in
unstimulated cells, and it isindependent of tyrosine
phosphorylation.89 The shuttlingof STAT3 is balanced by the nuclear
export and importsignals. Unlike STAT1, the C-terminal region of
STAT3(amino acids 321-771) contains the nuclear export activ-ity,
whereas the N-terminal part (1-320) has the nuclearlocalization
signal.89
Various importins mediate the nuclear import ofSTAT3.90,91 The
arginine residues in the coiled-coileddomain of STAT3 are involved
in both nuclear trans-location and CRM1-mediated STAT3 nuclear
exportand activation of STAT3.92 Importin-a3 mediatesSTAT3 nuclear
import independent of tyrosinephosphorylation.93
STAT trafficking determines cytokinesensitivity and
responses
Clearly, nuclear import and export of STAT areimportant
determinants of the response to cytokine, butrecent evidence
suggests that modulation of STAT traf-ficking is one mechanism by
which cytokine responsesmay be modulated and even fine-tuned.
Cytokine sen-sitivity has been found to be determined by the
nuclearexport of the relevant STAT proteins.94 The rate of
nucle-ocytoplasmic cycling of STATs is a novel mechanism bywhich
response to cytokine is determined. Cyotkine re-sponses are
affected when nuclear trafficking of STATis diminished. IFN-g
production and cell proliferationwere both impaired by the
impairment of IL-12–depen-dent STAT4 nuclear translocation.83
Dephosphorylation and proteolyticprocessing of STATs
Dephosphorylation of STATs involve tyrosine phos-phatases.
Several types of tyrosine phosphatases havebeen identified to
dephosphorylate STAT proteins, in-cluding SH2 domain-containing
tyrosine phosphatase 1(SHP1), SHP2, protein tyrosine phosphatase 1B
(PTP1B),T cell-protein tyrosine phosphatase (TC-PCP), CD45,PTPeC,
dual-specificity phosphatases, and low-molecu-lar-weight protein
tyrosine phosphatase.2 PhosphorylatedSTATs dimerize in a parallel
way and are subject to de-phosphorylation. However, a recent study
revealed duringthe activation-inactivation cycle of STAT1 that the
paral-lel dimerized STAT1 proteins not bound to DNA weresubject to
a conformational change of their dimer from aparallel to
antiparallel arrangement, which is more effi-ciently
dephosphorylated.95 This is another potentialmechanism by which
STAT signals may be regulated.
In addition to dephosphorylation by tyrosine phos-phatases,
proteolytic processing is another important stepin the deactivation
and downregulation of STATs. Thedephosphorylation and proteolytic
processes coordinateto regulate the deactivation of STAT proteins.
Ubiquitin/proteasome-mediated protein degradation is the
majorpathway for the inactivation of STAT5A, but in thecytoplasm,
tyrosine dephosphorylation is the dominantmechanism of inactivation
of STAT5A.96 A ubiquitin E3ligase, STAT-interacting LIM protein
(SLIM), was foundto regulate proteosome-mediated protein
degradation anddephosphorylation of STAT1 and STAT4.
Overexpres-sion of SLIM resulted in decreased STAT1 and
STAT4activity, whereas SLIM deficiency led to increasedSTAT1 and
STAT4 activity and IFN-g production.97 Inaddition to downregulating
STATs through degradativepathways, proteolysis of STATs can also
contribute tothe formation of novel STAT isoforms. Isoforms
ofSTAT3, STAT5, and STAT6 generated by proteolysishave been
reported.98-102 These isoforms are referred asSTATg, whereas the
isoforms generated by pre-mRNAalternative splicing are referred as
STATb. STATbisoforms have been found for STAT1, STAT3,STAT4, and
STAT5.73,103-107 The STAT5b acts as a
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dominant-negative variant of STAT5, whereas the STAT3band STAT4b
are not dominant-negative factors. STAT3bactivates specific STAT3
target genes and STAT4b acti-vates specific IL-12–induced gene
expression.104,107-111
Some STATb isoforms are involved in disease progressionin acute
myeloid leukemia.112 The STAT3g displayed dis-tinct expression
comparing to STAT3a and STAT3b dur-ing granulocytic
differentiation.99 The STAT5g generatedby protein processing has
distinct function in activationof IL-3 target genes.98 Proteolytic
processing of STAT6in mast cells generates truncated C-terminal
proteins(STAT6g) that lack the transactivation domain, whichcan
negatively regulate STAT6 function, decreasingIL-4–induced gene
expression.101,102
STAT FUNCTIONS
STATs and regulatory T cells
Regulatory T cells (Tregs) have been characterized as adistinct
subset of CD31CD41 T cells constitutively ex-pressing the alpha
chain of the high-affinity IL-2 receptor,CD25.113 Recently, a
unique transcription factor, forkheadbox P3 (FOXP3), was found to
be specifically expressed inmurine and human Tregs.114 Studies have
also shown thatectopic expression of FOXP3 in CD41 T cells was
suffi-cient to confer suppressive capabilities to CD41CD252
T cells.115 Functionally, CD31CD41FOXP31 Tregsact as natural
inhibitors of normal immune responses.Defects in Tregs have been
associated with a variety of im-mune pathologies. FOXP3-deficient
mice develop intensemultiorgan inflammation that is associated with
allergicairway inflammation. The resultant hyperimmunoglobuli-nemia
E and eosinophilia observed in these mice can bereversed by
concurrent STAT6 deficiency.116
Numerous studies have demonstrated that IL-2 isimportant in the
maintenance of Tregs. Neutralizingantibody-mediated IL-2 depletion
in mice results in auto-immune diseases associated with reduced
numbers ofFOXP3-expressing Tregs in the periphery.117 Disruptionof
IL-2 signaling in mice by knocking out IL-2, CD25,IL-2Rb, or STAT5
revealed an essential role for IL-2in the thymic development and
peripheral maintenanceof Tregs.118-123 Although IL-2 is not
required for FOXP3expression,124 it has been shown to upregulate
FOXP3expression in Tregs via activation of STAT3 andSTAT5.125
Natural Tregs constitutively express CD25(IL-2Ra), so they express
the complete high-affinity IL-2receptor complex (IL-2Ra, b, and gc)
and can presumablyrespond to physiologically low concentrations of
IL-2 andeffectively compete away IL-2 binding from naive T cellsto
receive IL-2-mediated survival signals.126,127
Activation of STAT5 is a primary mechanism of Tregdevelopment
stimulated by IL-2.128 Tregs were reduced inSTAT5A/5B deficient
mice, indicating that STAT5 isrequired for the maintenance of
tolerance in vivo.118,121
STAT5A has been shown to be involved in the develop-ment of
Tregs that modulate TH cells differentiation toTH2 cells.
129 The role of STAT5 is further highlighted
by the recent observation that Tregs are decreased inhuman
STAT5B deficiency.130
Cytokine signaling pathways are an integral part ofTreg biology.
IL-2 and other gc-dependent cytokines arecritical for the thymic
development and peripheral main-tenance of FOXP3-expressing natural
Tregs. The signal-ing pathway downstream of IL-2, including STAT5,
is animportant potential target for therapeutic
interventiondirected at Tregs. Other cytokines, including IL-10
andTGF-b, are important in the development of acquiredTregs.131
STATs and inflammation
Dysregulation of STAT pathways can yield
allergicinflammation.132 STAT6 is a key mediator of
allergen-induced airway inflammation and plays an essential rolein
TH2 cell trafficking, chemokine production, mucus pro-duction,
airway eosinophilia, and airway hyperresponsive-ness.133,134 STAT6
induces the expression of numerousgenes involved in allergic
inflammatory responses, includingeotaxin-1 and eotaxin-3, arginase
I, and P-Selectin.135-138
A recent study on adipocyte fatty acid-binding proteinaP2 showed
that it is required in the allergic airway inflam-mation and its
expression is induced via STAT6-depen-dent mechanisms.139
The role of STAT6 in the development of allergicinflammation is
complicated because both STAT6-depen-dent and STAT6-independent
pathways are involved, andSTAT6 can positively or negatively
regulate gene expres-sion.140,141 The STAT6-signaling pathway is
mainlyinduced by IL-4 or IL-13, but other factors can affectSTAT6
signaling. IFN-g inhibits STAT6-dependent sig-naling and gene
expression in human airway epithelialcells.142 Protein kinase C
zeta (PKCzeta)2/2 mice showedimpaired tyrosine phosphorylation and
nuclear transloca-tion of STAT6 and decreased allergen-induced
allergicairway responses.143 STAT6 is essential for the
develop-ment of allergic airway inflammation induced by
acuteallergen exposure but only partially mediates
airwayinflammation in a chronic model.144 Gene targeting stud-ies
showed that STAT6-deficient mice were protectedfrom the
IL-13–induced pulmonary responses, but devel-oped airway
hyperresponsiveness and peribronchial fibro-sis during chronic
fungal asthma.145,146 IL-5 has beenreported to reconstitute
allergen-induced airway inflam-mation and airway
hyperresponsiveness in STAT6-defi-cient mice supporting alternate
pathways.147
STAT6 is also involved in other inflammatory orimmune-related
diseases. STAT6-mediated TH2 im-munity is critical for the
development of autoimmunityin Graves hyperthyroidism.148 STAT6
expression isincreased in vascular smooth muscle cells from
coronaryarteries of ischemic heart disease, suggesting a role
ofSTAT6-mediated inflammation in atherosclerosis.44 Thedeficiency
of STAT6 and CD28 results in chronic ectopar-asite-induced
inflammatory skin disease.149
The importance of STAT1 in allergic inflammation wasdemonstrated
by the inhibition of allergen-induced airwayinflammation and airway
hyperresponsiveness by decoy
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oligonucleotide specific for STAT1.150 STAT3, STAT4,and STAT5
all play important roles in inflammation.STAT3 negatively regulates
STAT1-mediated inflam-matory gene activation in response to type I
IFNs.151
STAT3 is constitutively activated in intestinal T cellsfrom
patients with Crohn’s disease and growth hormonereduces STAT3
activation in Crohn’s colitis.152,153
Conditional knockout of STAT3 in endothelial cells re-vealed
that STAT3 is a critical anti-inflammatory mediatorin
endothelia.154 Cardiomyocyte-restricted knockout ofSTAT3 results in
higher sensitivity to inflammation, in-creased cardiac fibrosis,
and age-related heart failure.155
IL-12 and IL-18 attenuate airway hyperresponsivenessthrough
STAT4 activation,156 and STAT4 has been shownto modulate
allergen-induced chemokine production and air-way
hyperresponsiveness.157 Mucosal adenovirus mediatedIFN-g gene
transfer attenuated allergen-induced airway in-flammation and
airway hyperresponsiveness in an IL-12–and STAT4-dependent
manner.158 STAT4 is also involvedin the development of airway
inflammation in smokersand patients with chronic obstructive
pulmonary disease.35
STAT5A is indispensable in STAT6-independent TH2cell
differentiation and allergic airway inflammation.159
STAT5 is critical for IgE-induced mast cell activation
asSTAT5-deficient mast cells display decreased IgE-medi-ated
degranulation, leukotriene B4 production, cytokinesecretion, and
survival signals.160 Reduced colinic STAT5expression may contribute
to persistent mucosal inflam-mation in colitis.161
STATs and apoptosis
STATs have been implicated in the regulation ofapoptosis. IFN-g
suppresses TNF-related apoptosis in-ducing ligand-mediated
apoptosis through JAK-STATpathways.162 STAT1a overexpression
promotes apopto-sis with enhanced release of cytochrome c from the
mito-chondria and increased caspase-3 activity.163 In
contrast,inhibition of STAT3 induces apoptosis in prostate
cancercell lines.164 Serine phosphorylation of STAT3 is requiredfor
the suppression of apoptosis by the Bcl-2 family mem-ber Mcl-1.165
The function of STAT3 in anti-apoptosis issuppressed by GRIM-19, a
death-regulated gene product,which interacts with STAT3 and
inhibits STAT3 nucleartranslocation.166 STAT5 is critical for the
developmentand survival of mast cells as STAT5A/B-deficient
cellsdisplayed enhanced apoptosis.167 Similarly, the expressionof
dominant-negative forms of STAT5 in a pre-B cell lineresulted in
enhanced apoptosis.168 IL-4 mediates apoptosisof developing mast
cells and monocyte/macrophagesthrough a STAT6-dependent
mitochondrial pathway.169
STAT POLYMORPHISMS
Most STAT genetic polymorphism studies have focusedon STAT6.
Several polymorphisms have been identified inSTAT6 genes. Variation
in the dinucleotide (GT) repeat se-quence in exon 1 of the STAT6
gene has been associatedwith atopic asthma and increased total
serum IgE level
in a British population.170 Studies done in vitro examiningthe
functional significance of this variation showed thatthe GT repeat
modulates promoter activity by alteringthe binding stability of
nuclear factors.170 In a Caucasiansib-pair study, the GT repeat in
exon 1 of STAT6 was as-sociated with eosinophilia and total serum
IgE levels,but not with asthma.171 In a Japanese population, theGT
repeat polymorphism in exon 1 in combination withhomozygosity for
the 2964G allele was significantlyoverrepresented in subjects with
allergy.172 However, ina study of Chinese patients with atopic
dermatitis, no asso-ciation of the STAT6 GT repeat polymorphism
wasfound.173 Specific haplotypes of a polymorphic CA repeatin the
proximal promoter region and in the 59 untranslatedregion of STAT6
were found to be associated with asthmain an Indian population.174
A separate study on 6 polymor-phisms of the STAT6 gene in a German
population re-vealed significant associations of specific
haplotypes andsingle nucleotide polymorphisms (SNPs) with elevated
se-rum IgE, specific sensitization, and/or asthma risk.175
InFinnish families with asthma, polymorphisms of STAT6or STAT4 were
not found to be associated with asthmaor elevated serum IgE
levels.176 In a British patient popu-lation, a STAT6 39
untranslated region polymorphism wasassociated with the risk and
severity of nut allergy.177
Cumulatively, there is strong evidence for genetic associa-tions
of STATs with atopic disease. The mechanisms bywhich these STAT
polymorphisms confer risk for differentatopy phenotypes is not yet
clear, although several havebeen found to have functional
significance. STAT6 poly-morphisms are also associated with other
human diseases.One study showed that the STAT6 G2964A
polymorphismis associated with Crohn’s disease in German patients,
butother studies did not find this relationship in Dutch orChinese
populations.178-181
In addition to STAT6, polymorphisms of STAT3 andSTAT4 have also
been studied in atopic disorders.Analysis of STAT3 polymorphisms
revealed associationof STAT3 SNPs with lung function (FEV1) in
adults andchildren with asthma.182 Among 12 SNPs of STAT4
ana-lyzed, 1 SNP in intron 11 and 2 haplotypes were found tobe
associated with Dermatophagoides farninae (Der p)-or
Dermatophagoides pteronyssinus (Der f)-specific IgE,suggesting a
role for these STAT4 polymorphisms in theproduction of IgE in
response to mite allergens inasthma.183 No association of
polymorphisms of STAT4with asthma or elevated serum IgE level was
identifiedin Finnish families with asthma.176
PHARMACEUTICAL TARGETINGOF JAK-STAT
Progress in our understanding of inflammatory signal-ing
pathways has identified new targets, including pathwaysinvolving
JAK-STAT. Inhibitors have been developed thatmight be used
clinically for inflammatory diseases.184 Ofthe 4 JAKs, JAK3 has
been the focus of most interest interms of drug development because
of its selective
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FIG 3. Potential pharmaceutical targeting of the STAT-signaling
pathway.
expression in T cells and its activation by IL-2. JAK3
iscritical for gc signaling (utilized by IL-2, IL-4, IL-7, IL-9,and
IL-15) and constitutively associates with the gc chain.JAK3
deficiency accounts for approximately 7% to 14% ofsevere combined
immunodeficiency cases.185-190 Impor-tantly, JAK3 deficiency does
not result in widespread plei-otropic defects, so a highly specific
JAK3 inhibitor shouldalso have limited and precise effects. An
orally availableselective JAK3 antagonist has been
developed.191
The drug, CP-690550, has an IC50 of 1 nmol/L191 and
isapproximately 30-fold and 100-fold less potent for JAK2and JAK1,
respectively. CP-690550 showed remarkableefficacy in the prevention
of graft rejection in a primatemodel,191 and the efficacy observed
with CP-690550surpassed that obtained with cyclosporine A in the
samemodel. CP-690550 potently blocks IL-2 signaling andresponses,
but does not effect T-cell receptor signaling.Indeed, the
combination of a calcineurin inhibitor, whichwould block signals
emanating from the T-cell receptor,and CP-690550 reveal synergistic
effects.192 CP-690550did not cause granulocyte or platelet
deficiency. Therewas a trend in the reduction of CD81 T cells, but
nosignificant decline in total T lymphocytes. CP-690550 iscurrently
being evaluated in models of autoimmunity.
IL-4 is a critical cytokine in promoting TH2 differenti-ation
and the allergic response. Because IL-4 utilizes thegc chain and
JAK3 for signaling, a JAK3 inhibitor wouldbe expected to antagonize
IL-4. Thus, a JAK3 antagonistmay be useful in allergic disorders.
CP-690550 was alsofound to inhibit delayed-type hypersensitivity,
and its ef-fects were reversible when the drug was
discontinued.192
IL-9 has been reported to contribute to the developmentof asthma
and has been suggested as a potential targetfor asthma
treatment.193 Antagonizing the effects of IL-9with a JAK3
antagonist could be of use in treating asthma,although the
importance of this cytokine in asthma iscontroversial.194-196 Aside
from JAK3, another possibleJAK to target would be Tyk2. Tyk2 is
involved in IL-13
signaling and is necessary for the induction of IL-13–mediated
goblet cell hyperplasia in the airways.197,198
At present, targeting STATs has met with less successthan
targeting JAKs, because it has been simpler toidentify small
molecules that interfere with JAK catalyticactivity. However,
because of their crucial selectivefunctions, targeting STATs
remains an attractive goal.Potential mechanisms to block STAT
activity includeblocking their recruitment to cytokine receptors,
dimeriza-tion, nuclear import, DNA binding, dephosphorylation,
ornuclear export (Fig 3).2
In terms of allergic disease, 2 STATs that might beuseful to
target are STAT4 and STAT6.2 These STATs arecrucially important for
the differentiation of TH cells. IL-4activates STAT6 and promotes
the differentiation of TH2cells that promote allergic responses.
Conversely, IL-12activates STAT4 and drives the differentiation of
naiveT cells into TH1 cells that produce IFN-g. As discussedabove,
constitutive activation of STAT3 and STAT5has been noted in several
tumors. Targeting these STATsfor the treatment of cancer is of high
interest.199,200
Antagonizing the expression or activation of STAT3induces
apoptosis of cancer cells, inhibits angiogenesis,and promotes the
elimination of cancer cells by activatingdendritic cells.184
However, STAT3 deficiency is embry-onically lethal.2 The
therapeutic window for antagonizingSTAT3 function may be
narrow.
Because the JAK-STAT pathway is central to so manyfundamental
biologic processes, it is not surprising that theregulation of STAT
function is a tightly regulated process.Indeed, several mechanisms
have been described thatserve to regulate the JAK-STAT pathway at
differentpoints along the cascade, and these regulatory
mechanismsare potential targets to modulate STATs.2 The
importanceof STATs is further highlighted by their role in
themechanisms by which other agents mediate their
effects.Cyclooxygenase-2 (COX-2) inhibitors prevent experi-mental
allergic encephalomyelitis, a TH1-cell–mediated
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autoimmune disease model of multiple sclerosis, by reduc-ing
IL-12 production and decreasing IL-12-induced T-cellresponses,
through inhibition of STAT3 and STAT4 tyro-sine phosphorylation.201
The 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor,
Atorvastatin (Pfizer, NewYork, NY), induces STAT6 phosphorylation
and TH2 cy-tokine secretion while inhibiting STAT4
phosphorylationand TH1 cytokine secretion.
202 The direct anti-inflamma-tory effects of statins are
achieved by reducing IL-6-induced phosphorylation of STAT3 in
hepatocytes.203
Paclitaxel (Myers Squibb Co, New York, NY), a micro-tube
stabilizer used in anticancer therapy, significantly de-creases the
nuclear translocation of STAT protein inadipocytes without
effecting tyrosine phosphorylation.204
Given the central role of the JAK-STAT signaling in bio-logic
processes involved in all phases of the immune re-sponse and the
successful generation of a selective JAKinhibitor, STATs will
continue to be the focus of consider-able attention as potential
therapeutics.
CONCLUSION
STAT proteins are critical for many intersecting anddivergent
pathways that contribute to allergic inflamma-tion. Their
expression, and consequently their impact,is ubiquitous, impacting
a variety of cell types critical toallergy including epithelial
cells, mast cells, lymphocytes,dendritic cells, and eosinophils.
Dysregulation of STATsignaling has been found in human and animal
studies ofallergic disease. There is considerable potential of
thesepathways as a target for therapeutic intervention.
Someprogress has already been made in targeting JAK-STAT;however,
considerable work remains for us to fullydelineate the mechanisms
by which these molecules areregulated and the optimal targets for
intervention.
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Signal transducer and activator of transcription signals in
allergic diseaseOverview of stat proteinsStructureSTAT
PhosphorylationSTAT cofactorsSTAT nuclear import and exportSTAT
trafficking determines cytokine sensitivity and
responsesDephosphorylation and proteolytic processing of STATs
Stat functionsSTATs and regulatory T cellsSTATs and
inflammationSTATs and apoptosis
Stat polymorphismsPharmaceutical targeting of
jak-statConclusionReferences