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Glucocorticoids: mechanisms ofaction and
anti-inflammatorypotential in asthma
V. H. J. van der Velden
Department of Immunology, Erasmus University,PO Box 1738, 3000
DR Rotterdam, The Netherlands
Te l: (+31) 10 408 7192Fax : (+31) 10 436 7601Email:
[email protected]
GLUCOCORTICOIDS are potent inh ibitors of in flam m
atoryprocesse s and are w ide ly used in th e treatm ent ofas thm
a. Th e an ti-inflam m atory effects are m ediatedeither by direct
binding of the glucocorticoid/gluco-corticoid receptor com plex to
glucocorticoid respon-sive e lem ents in th e prom oter region of
genes , or byan in te raction of th is com plex w ith other tran
scrip-tion factors , in particular activating prote in-1 ornuclear
factor -k B. Glucocorticoids in hibit m anyin flam m ation-associa
ted m olecules such as cyto-kines , chem okines , arachidon ic acid
m etabolites , andadhesion m olecules . In contras t, an ti-inflam
m atorym ediators often are up-regulated by glucocorticoids .In
vivo studies have shown that tr eatm ent of asth -m atic patients w
ith in haled glucocorticoids in h ibitsthe bronchial in flam m
ation and s im ultaneouslyim proves th eir lung function . In th is
r evie w , ourcurren t kn owledge of th e m echan ism of action
ofglucocor ticoids and their anti-in flam m atory poten tialin as
thm a is described. Since bronch ial epithe lialcells m ay be im
portan t targe ts for glucocorticoidtherapy in asth m a, the
effects of glucocor ticoids onepithe lial ex pre ssed inflam m
atory genes w ill beem phasized.
Key words : Glucocorticoids, Asthma, Bronchial epithe lialce
lls, Inflammation
Introduction
Glucocorticoids are hormones synthe sized in theadrenal cortex
and sec rete d into the blood, w here theleve ls of glucocorticoids
fluctuate in a circadianmode . In humans, the naturally occurring
gluco-corticoid is hydrocortisone (cortisol), w hich is
syn-thesized from its precursor cortisone .
The be neficial e ffec ts of glucocorticoids in as th-matic
patients w ere first de scribed in 1950.1 Sincethen on, many studie
s have focused on the ther-apeutic potential of glucocorticoids.
Several syntheticglucocorticoids, much more potent than cortisol
andw ithout the unw anted mine ralocorticoid side e ffec ts,have
been deve loped. Now adays, glucocorticoids arepow erful agents in
the tre atment of inflammatorydiseases and are by far the most
effective anti-inflammatory drugs used in the treatment
ofasthma.
Mechanism of ActionAlthough glucocorticoids have been know n for
a longperiod of time , the ir prec ise mechanism of ac tion isstill
not complete ly unde rstood. However, recentstudies have inc reased
our understanding of theircomplex mechanisms of action.
Glucocorticoid receptor
To ex ert the ir effe cts, glucocorticoids ne ed to bind toa
spec ific cytoplasmic glucocorticoid receptor (GR).Almost all ce
lls of the body ex pre ss the GR, but thenumber of re ceptors may
vary be tw een differe nt ce lltype s.2 Cloning of the GR has re
vealed that the GRcons is ts of approx imately 800 amino ac id
residues,and that ce rtain areas of the molecule show homol-ogy w
ith othe r steroid re ceptors, receptors forthyroid hormones, and
receptors for re tinoic ac id.3 –7
All members of the nuclear hormone receptor familyshare a charac
teristic three-domain structure , firstdesc ribed for the human GR.
The C-terminal domainis equal in size in all nuclear receptors
studied (about250 amino ac ids) and its main function is to bind
thesteroid.8 It also contains the binding site s for the heatshock
prote ins (hsp) 90.9,1 0 Removal of the steroid-binding domain
results in a constitutively ac tive GRmolecule, indicating that
this part of the moleculeacts as a repressor of the
transcription-activationfunction. The most conserved central domain
isinvolved in direct binding of the re ceptor to DNA. Itcontains tw
o distinct loops of prote in, each bound attheir base via four
cyste ine re sidue s to a single zincion, the so-called zinc
fingers.1 1 These zinc cluste rsare involved in binding of the GR
to the major grooveof the DNA double he lix and play a role in
dimeriza-
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Mediators of Inflammation, 7, 229–237 (1998)
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tion of tw o GR molecule s.1 2,1 3 In addition, the
centralDNA-binding domain has a transcription-activationfunction.4
,14 The ste roid-binding and DNA-bindingdomains are separated by
the ‘hinge-region’, w hichcontains sequence s that are important
for nucleartranslocation and dimerization.9,10 The N-te
rminaldomain is ex treme ly variable in size (24–600 aminoacids).
Its pre cise role is still uncertain, but it isrequired in transc
riptional activation.15
Tw o different forms of the human GR have be endesc ribe d.3 ,1
6 These tw o highly homologous isoforms,te rmed GRa and GRb , are
gene rated by alternativesplic ing of the human GR pre -mRNA. The
GRbisoform diffe rs from the GRa isoform only in itsC-terminal
domain, in w hich the last 50 amino ac idsof the latte r are
replaced by a unique 15 amino ac idsequence . How ever, this re
placement has dramaticfunctional consequence s, since the GRb
isoform isunable to bind glucocorticoids and to
transduceligand-dependent transac tivation. How eve r, the
phys-iological significance of the GRb isoform remainsquestionable,
s ince some recent studies indicate thatthis form is not conse rved
among spec ie s and nodominant negative inhibition of GRa activity
could befound.17 ,1 8 Nevertheless , abundant ex pre ssion of
GRbprote in can be found in the epithe lial cells lining thete
rminal bronchioli of the lung.19
The ex press ion of the GR may be re gulated bynumerous fac tors
e ither at the transc riptional, transla-tional or
post-translational leve l.2 0,21 Glucocorticoidshave be en show n
to dow n-regulate the ex pression ofthe GR, both in v itro and in
vivo .22 ,23 In contrast,inflammatory mediators like interleukin
(IL)-1 b , IL-4,tumour ne crosis fac tor (TNF)-a , lipopolysac
charide(LPS) and interferon (IFN)-g have been show n toinc re ase
glucocorticoid binding in vitro .24 – 28 How -eve r, the inc rease
in GR numbers may be ac com-panied by a reduced affinity for
glucocorticoids.24 ,2 8
Analysis of GR localization in normal and asthmaticlung has not
revealed differenc es in the leve l or sitesof GR ex pre ssion.2
9
Regulation of gene transcription
In the absence of glucocorticoids, the GR is presentin the
cytoplasm of the cell as a he te ro-oligomercons is ting of the GR
itse lf, tw o molecule s of hsp90, one molecule hsp 70, and one
molecule of hsp56 (w hich probably does not interact w ith the
GRitself, but interacts w ith hsp 90).30 – 3 4 Glucocor-ticoids
enter the cytoplasm of the ce ll by passivediffusion through the
cell membrane. In the cyto-plasm they bind to the GR complex , w
hich subse-quently undergoes conformational change s, re sult-ing
in the dissoc iation of the hsp 90 and hsp 56molecules . Upon this
activation, the glucocorticoid-GR complex passe s the nuc lear
membrane, entersthe nuc leus, and the hsp 70 molecule is dissoc
iated.
Furthe rmore , in the nucleus liganded GR form hom-odimers (Fig.
1).
Within the nucleus, the GR homodimers mayregulate gene transc
ription in seve ral ways: (1) viabinding of the glucocorticoid-GR
complex to spec ificDNA sequences, the reby directly ac tivating or
re pre s-sing gene s; (2) via inte raction w ith other
transcriptionfactors; and (3) via modulating the stability of
specificmRNA molecule s.3 5 – 3 9
Bin ding to DNA s eque nce sSeve ral steroid-re sponsive genes
contain glucocor-ticoid re sponsive e lements (GRE) in their
promoterregion.3 5,4 0 Binding of GR homodimers to GRE mayeither re
sult in transcriptional activation of the gene(via a po s itive
GRE) or repression of the gene (via anega tive GRE) (Fig. 1). The
consensus sequence for(positive) GRE is the palindromic
15-base-pairsequence GGTACAnnnTGTTCT, w hereas the negativeGRE has
a more variable sequence.36 The rate oftransc riptional regulation
of steroid-re sponsive genesis dependent on both the numbers of
GRE, the affinityof the glucocorticoid-GR complex to the GRE, and
theposition of the GRE re lative to the transcriptional startsite .
Binding of the complex to GRE may re sult inconformationa l change
s in the DNA and ex posure ofpreviously masked areas, re sulting in
increased bind-ing of othe r transcription factors.4 1– 44
In te ra c tio n w ith o th e r tra n s criptio n fa c to r
sMany ste roid-responsive gene s do not have GRE intheir promoter
region. How ever, binding site s forothe r transcription factors,
including nuclear factor(NF)-k B, ac tivating prote in (AP)-1, and
cAMP-respon-sive e lement binding protein (CREB), often can
befound.45
V. H. J. van de r Ve lden
230 Mediators of Inflammation · Vol 7 · 1998
FIG. 1. Schematic representation of the cellular events
afteradministration of glucocorticoids (adapted from Ref. 39).
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AP-1, w hich is a dimer of tw o proto-oncogene s(members of the
c-jun and c-fos family),46 ,47 isinvolved in the regulation of
several genes, includingadhesion molecules and cytokines (review ed
in Ref.47). Direct protein–prote in inte raction betw een AP-1and
the glucocorticoid-GR complex results in rec ipro-cal repre ssion
of one another’s transc riptional activa-tion by pre venting
binding of the AP-1 and gluco-corticoid-GR complex to AP-1 sites
and GRE,respective ly (Fig. 1).3 7,4 8,4 9
Comparable to AP-1, NF-k B (a hete rodimer of p50and p65
subunits5 0,51 ) re gulate s the transcription ofseveral gene s
involved in inflammatory reac-tions.5 0,52,5 3 In unstimulated ce
lls , NF-k B is re tained inthe cytoplasm of the cells through the
interaction w iththe inhibitor s Ik Ba and Ik Bb .5 4 – 56 Upon
cell stimula-tion, for ex ample by IL-1 b or TNF-a , I k B are
rapidlyphosphorylated, ubiquitinated, and consequently pro-te
olysed.53 ,57 The liberated NF-k B dimers translocateto the nucleus
w here they can ac tivate target genes.Glucocorticoids may inhibit
NF-k B-stimulated gene sby a direct interaction betw een the
glucocorticoid-GRcomplex and the p65 subunit of NF-k B, re sulting
intransrepre ssion (Fig. 1).5 1,5 5,5 8,59 Furthe rmore ,
gluco-corticoids may indirec tly antagonize NF-k B mediate dtransc
ription by up-regulating the synthesis of theinhibitory protein Ik
Ba , w hich traps NF-k B in inac tivecytoplasmic complex e s.39 ,54
,5 5 A large number ofimmunoregulatory genes, w hose ex pre ssion
isinduced by a variety of pro-inflammatory mediators,contain NF-k B
sites in their promote rs/re gulatoryregions. Therefore , it is no
w onder that glucocorticoidshave been found to prevent the ex pre
ssion of the segenes, including those coding for IL-1 b , IL-2,
IL-6, IL-8,monocyte chemoattrac tant prote in (MCP)-1,
RANTES(Regulated upon Activation, Normal T ce ll Ex pre ssed,and
presumably Sec rete d), granulocyte macrophagecolony-stimulating
factor (GM-CSF), the IL-2 receptor,inte rcellular adhe sion
molecule (ICAM)-1, andE-se lectin (review ed in Ref. 45). Probably,
interactionsbetw een glucocorticoids and NF-k B or AP-1 w illex
plain most of the anti-inflammatory and immuno-suppressive
activities of glucocorticoids.
An inte rac tion be tw een CREB and the gluco-corticoid-GR
complex has also been suggeste d.6 0,6 1
b -agonists, w hich are used as bronchodilators in thetre atment
of asthma, inc rease cAMP formation andsubsequently ac tivate CREB.
Therefore , s imultaneoustre atment of as thmatic patients w ith
glucocorticoidsand b -agonists may result in reduced re sponsivene
ssof the airw ays for steroids.6 1– 63
Mo dula tio n o f m RNA s ta bility.A third mechanism by w hich
glucocorticoids mayregulate the synthesis of prote ins is via
enhancedtransc ription of spec ific ribonuclease s w hich are
ableto degrade mRNA containing constitutive AU-richsequence s in
the untranslated 3 9 -re gion.64 Such gluco-
corticoid-mediated modulation of post-translationalevents
(resulting in decreased mRNA stability andreduced half-life time)
has be en observed for IL-1 b , IL-6 and GM-CSF.6 5,6 6
Glucocorticoid Regulated GenesGlucocorticoids are able to
modulate the transcrip-tion of a varie ty of gene s, including
cytokines andchemokines, re ceptors, enzymes, adhesion mole-cules ,
and inhibitory prote ins (Table 1). Since epithe-lial c ells may be
one of the most important targets forglucocorticoid the rapy in
asthma, the effe cts ofglucocorticoids on epithe lial ex pressed
inflammatorygenes w ill be emphas ized in this re view.
Cytokines and chemokines
Glucocorticoids inhibit the transcription of mostcytokines and
chemokines that are re levant in asthma,including IL-1 b , TNF-a ,
GM-CSF, IL-3, IL-4, IL-5, IL-6, IL-8, IL-11, IL-12, IL-13, RANTES,
eotax in, and mac ro-phage inhibitory prote in (MIP)-1 a .45 ,66 In
general,reduced synthe sis of these mediators may re sult in adecre
ased re cruitment and ac tivation of leukocytes,also indire ctly
due to e ffec ts on adhe sion molecule sand cell survival. Since
many cytokine gene pro-mote rs do not contain a ne gative GRE, the
effects ofglucocorticoids on cytokine and chemokine produc-tion are
probably mediated via an e ffec t on a critic altransc ription
factor (e spec ially NF-k B and AP-1).6 7
Cross-signalling betw een NF-k B and AP-1 w ith
gluco-corticoid/GR complex have indeed be en demon-strated in
bronchial ep ithe lial cells.6 7
Glu co co rtico id a ctio n in a s th m a
Mediators of Inflammation · Vol 7 · 1998 231
Table 1. Influence of glucocorticoids on the synthesis
ofproteins with inflammatory effects by bronchial
epithelialcells
Protein Glucocorticoideffect
CytokinesIL-1b , IL-6, IL-11, TNF- a , GM-CSF ¯IL-10, LIF ?G-CSF
=
ChemokinesMCP-1, eotaxin, IL-8, RANTES, MIP-1a ¯
ReceptorsNK, GR ¯IL-1R II, IL-6R, b 2-adrenergic receptor
EnzymesiNOS, COX-2, cPLA2 ¯NEP
Adhesion moleculesICAM-1 ¯
Inhibitory proteinsLc-1 =/IL-1RA type I, SPLI
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Bronchial epithelial cells are capable of producing avarie ty of
cytokine s and chemokine s that may contrib-ute to the initiation
and pe rpetuation of airw ayinflammation. Several studies have show
n that cyto-kine-induced ex pression of eotax in, IL-6, IL-8,
GM-CSF, and RANTES can be diminished by gluco-corticoids in v itro
.68 –76 In contrast, glucocorticoidsdid not modulate the sec re
tion of G-CSF by humanbronchial epithelial cells.7 6 In v ivo
studie s haveshow n that treatment w ith inhaled steroids decre ase
sboth the ex press ion of GM-CSF,77 IL-1 b ,78 IL-8,79 andRANTES80
by the bronchial ep ithe lium, toge the r w iththe number of ac
tivated eosinophils in theepithe lium.
Receptors
Glucocorticoids may modulate the ex press ion ofseveral re
ceptors. The ex pre ssion of the neurokinin(NK)1 re ceptor, w hich
mediate s many effects ofsubstance P (SP) in the airw ays and is be
lieved to beup-regulated in asthma,8 1 is dow n-re gulated by
gluco-corticoids.8 2 Since the NK1 re ceptor gene promoterregion
has no GRE but has an AP-1 re sponse e lement,this e ffec t
probably w ill be mediated via an inte r-action of the
glucocorticoid-GR complex w ith AP-1.
In contrast to NK1 re ceptors, ex press ion of theb 2-adrene
rgic receptor is increased by glucocor-tic oids.8 3 Since the human
b 2-adrene rgic receptorgene contains three potential GRE, this
effect ofglucocorticoids probably is a dire ct one .83
Up-regula-tion of b 2-adrene rgic re ceptors by glucocorticoidsmay
be re levant in as thma as it may prevent dow n-regulation in re
sponse to prolonged tre atment w ithb 2-agonists .
84
The IL-1 receptor type II, w hich func tions as adecoy re
ceptor,8 5 may also be up-regulated by gluco-corticoids, there by
re ducing the functional ac tivity ofIL-1 agonists.8 6,8 7 Soluble
TNF-re ceptor type I (p55)re lease by human bronchial epithelial c
ells, bothconstitutive as w ell as IL-1 b -induced, has been show
nto be re duced by glucocorticoids.8 8 In contrast,glucocorticoids
up-re gulate the ex pre ssion of IL-6receptors in rat hepatoma and
human epithelialce lls .89 ,90 Thus far little is know n about this
proce ss inhuman bronchial epithe lial ce lls, w hich
constitutivelyex pre ss these re ceptors.91
Glucocorticoids also modulate the ex pre ssion oftheir ow n
receptor. In a re cent study it w as show nthat ex press ion of the
a -form (but not the b -form) ofthe GR in human bronchial ep ithe
lial ce lls w as dow n-regulated in healthy subjects after 4 weeks
of budeso-nide inhalation.2 3
Enzymes
Glucocorticoids inhibit the synthe sis of severalinflammatory
mediators implicated in the pathogene-
sis of asthma through an inhibitory effect on enzymeinduction.
The synthe sis of inducible nitric ox idesynthase (iNOS) by human
airw ay epithelial cells isinhibited by glucocorticoids, both in
vitro and inv ivo .92 – 9 4 This effe ct seems to be mediated
viainactivation of NF-k B.9 5,9 6 Since nitric ox ide (NO)may
contribute to skew ing of Th lymphocytestow ards a Th2 phenotype ,
there by promoting IgEproduction and eosinophil rec ruitment,
inhibition ofiNOS may be of importance in anti-inflammatorytherapy
in as thma.9 7
Glucocorticoids also inhibit the gene transcriptionof a
cytosolic form of phospholipase A2 induced bycytokine s98 and
inhibit the gene ex pre ssion ofcycloox ygenase-2, re sulting in
reduced formation ofprostaglandins and thrombox anes.99
In contrast to the enzymes mentioned above,glucocorticoids have
be en show n to increase theex pre ssion of neutral endopeptidase
(NEP),10 0 –10 2
thereby pote ntially limiting neurogenic inflammatoryresponses.1
03 In ac cordance w ith the se results, it w asfound that the ex
press ion of NEP on bronchialepithe lial c ells w as higher in as
thmatic s treatedw ith steroids compared w ith nonste
roid-treatedasthmatics.1 04
Endothelins
Endothelins are a family of highly homologous21-amino ac id
peptide s, charac terized by tw o intra-chain disulphide chains, a
hairpin loop cons isting ofpolar amino ac ids, and a hydrophobic
C-te rminalchain.10 5 Human bronchial epithelial c ells have be
enshow n to produce ET-1,1 06 –1 08 w hich promotes theprolife
ration of smooth muscle ce lls , is a pote ntconstrictor of both
vascular and non-vascular smoothmuscle ce lls , inc reases the se
cretion of mucus, andmay ac tivate inflammatory ce lls.1 05 ,1 07
,10 9 ET-1 alsostimulates collagen gene ex pression and through
itsinhibitory ac tions on collagenase w ill promote airw ayw all
collagen deposition, there by contributing toairw ay w all
thickening w hich underlies bronchialhyperresponsiveness.11 0 –11 2
Inc re ased leve ls of ET-1-immunoreac tivity we re detected in
airw ay epithe-lium and vascular endothelium of bronchial
biopsyspecimens from nonste roid-tre ated asthmatic s com-pared w
ith healthy subjects .10 6,1 13 ,11 4 In contrast, noincre ased
ET-1 ex pression w as found in the bronchialepithe lium of
asthmatic patients treated w ithglucocorticoids.11 5
Adhesion molecules
Adhesion molecules play an important role in therec ruitment of
inflammatory ce lls to the inflamma-tory locus. Ex pression of
adhesion molecule s onendothelial, epithelial or inflammatory ce
lls is often
V. H. J. van de r Ve lden
232 Mediators of Inflammation · Vol 7 · 1998
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induced by cytokine s, w hereas glucocorticoidsreduce surface ex
pression of adhe sion molecules.This effect may be due either to
inhibition of cytokinesynthesis or to a direc t effect of
glucocorticoids onadhesion molecule gene transcription. It has be
enshow n that the ex pression of ICAM-1, endothelialleukocyte
adhesion molecule (ELAM)-1, and E-selec tinis dow n-re gulated by
ste roids.11 6 Basal and cytokine-stimulated ICAM-1 ex pre ssion on
human bronchialepithe lial c ell lines is inhibited by glucocor-tic
oids.1 17 ,11 8 Howeve r, inhaled glucocorticoids didnot modulate
ICAM-1 ex pre ssion by bronchial epithe-lial ce lls from asthmatic
s in vivo .11 9
Eosinophil adhe sion to cytokine-stimulated bron-chial ep ithe
lial c ells w as show n to be inhibited by thesynthetic
glucocorticoid dex amethasone .120 Althoughcytokine-activated
epithelial c ells show ed increasedex pre ssion of ICAM-1, this
molecule did not seem tobe involved in the dec reased adhe sion of
eosinophilsobserved in the presenc e of dex amethasone .12 0
Inhibitory proteins
The anti-inflammatory e ffec ts of glucocorticoids maybe
mediated by increasing the production of inhibi-tory prote ins,
such as lipocortins. Lipocortins aremembers of a supe rfamily of
proteins characterizedby the ir ability to bind calcium and anionic
phospho-lipids, now know n as the ‘annex ins’.12 1,12 2 In
severalce ll type s, but not all, glucocorticoids are inducers
oflipocortins, w hich have an inhibitory effec t on theactivity of
phospholipase A2 .
123 ,1 24 As a re sult, thesynthesis of lipid mediators,
including prostaglandinsand e icosanoids, w ill be re duced. How
ever, in humanbronchial epithelial c ells glucocorticoids do not se
emto up-regulate the ex pre ssion of lipocortins.12 5 Fur-thermore
, no significant difference w as foundbetw een lipocortin-1
concentration in BAL fluid fromasthmatic patients re ce iving
inhaled glucocorticoidtherapy and those w ho were not treated w
ithglucocorticoids.12 6
Recently, glucocorticoids have also been show n toinc re ase the
ex pre ssion of intracellular IL-1 receptorantagonist type I by
human bronchial epithelial c ellsin vitro .1 27 Increased
production of this mediatormay inhibit the effe cts of IL-1
agonists , the rebyreducing inflammation. Howeve r,
glucocorticoidtreatment of asthmatic patients did not affe ct theex
pre ssion of IL-1 receptor antagonist by the bron-chial epithe
lium.78
To provide prote ction against potentially injuriousagents, airw
ay epithe lial cells se cre te a number ofmediators, including
antiprote ase s. Secretory leuko-cyte protease inhibitor (SLPI) is
the pre dominantantiprotease in the airw ays. Its ex pre ssion has
be enshow n to be inc reased in airw ay epithelial ce lls
afterstimulation w ith glucocorticoids.12 8
Cellular and Clinical Effects ofGlucocorticoids in AsthmaSeve
ral s tudie s have determined the effe cts of
inhaledglucocorticoids on bronchial inflammation, e ithe r
bymeasurements in BAL fluid, sputum, or ex haled air, orby
performing bronchial biopsie s. Although differ-ences can be
observed betw een differe nt trials , the sestudies have confirmed
that glucocorticoid treatmentof asthmatic patients reduces the
number and activa-tion of inflammatory ce lls in the airw ays,
togetherw ith an improvement of lung func tion. Now adays,the
potent anti-inflammatory ac tions of glucocor-ticoids are thought
to underlie the clinical e ffic acy oforal glucocorticoids.1 29
Effects of glucocorticoids on immunopathology
Inhaled glucocorticoids decre ase the number andactivation
status of most inflammatory cells in thebronchus, including mast
cells, dendritic ce lls , eosino-phils , and T lymphocytes .
Changes in cellular infiltra-tion are ac companied by modulated ex
press ion ofseveral cytokines. Inhaled glucocorticoids have be
enshow n to decrease mRNA ex pre ssion of GM-CSF, IL-13, IL-4, and
IL-5, w hereas mRNA leve ls of IL-12 andIFN-g inc reased, sugge
sting a shift from a Th2-tow ards a more Th1-like environment.77
,13 0,1 31
Glucocorticoid tre atment is as sociated w ith areduction in m a
st c e ll numbers in the bron-chus7 9,1 29 ,1 32 –13 5 and w ith
reduced mast ce ll asso-ciated mediators in BAL fluid.13 5,1 36
This may be dueto a re duc tion in IL-3 and ste m ce ll factor
production,w hich are necessary for the survival of mast c ells
intissue. The (IgE-dependent) re lease of mediators frommast cells
does not se em to be affec ted by gluco-corticoid treatment.1 37,13
8
Dendritic cells play an important role in presentingantigens to
(naive) T ce lls .139 ,1 40 Inhaled gluco-corticoids have been show
n to re duce the numberof dendritic c ells in the human
bronchialepithe lium.1 41
Increased numbers of eos inophils are a prominentfeature of
asthmatic airw ays.14 2 –148 In v itro studie shave show n that
many eosinophil functions, includ-ing adhe renc e and chemotax is,
are diminished follow -ing glucocorticoid treatment.1 38 How ever,
most datasuggest that eos inophil re sponses to steroids are
likelyto be indire ct, s ince eosinophil func tion is markedlyaffec
ted by cytokine s e laborated from T lymphocytes(IL-3, IL-4, IL-5,
GM-CSF), endothelial c ells (GM-CSF)and epithelial c ells
(GM-CSF).1 49 –1 53 In vivo studie sindicate that tre atment w ith
inhaled steroids re ducesthe number of eosinophils and
eosinophil-re latedmediators in BAL fluid79 ,1 48,15 4 and the
numberof (activated) eosinophils in bronchial biop-sie s.79 ,1 29
,13 2,1 33 ,1 55 Recently, induced sputum hasbeen suggeste d as a
useful tool for evaluating the
Glu co co rtico id a ctio n in a s th m a
Mediators of Inflammation · Vol 7 · 1998 233
-
effects of the rapy on airw ay mucosal inflammation.Thus far,
most studie s have focused on the pre senc eof eosinophils and
eosinophil-re lated mediators . Inaccordance w ith the findings in
BAL fluid andbronchial biopsie s, glucocorticoid treatment w
asassociated w ith a re duction in sputum eosinophilnumbers ,
eosinophil cationic protein (ECP), andeosinophil pe rox idase
(EPO).156
Glucocorticoids also re duce the number of acti-vated T
lymphocyte s in bronchial biopsie s and BALfluid.1 29 ,13 3,1 34 ,1
55,1 5 7 In addition, inhaled corticoste-roids reduced the number
of ce lls ex pressing mRNAfor IL-4 or IL-5, and increased the
number of cellsex pre ssing mRNA for IFN-g ,1 31 ,13 2 the reby
favouringthe deve lopment of Th1 cells.15 8
In addition to the e ffec ts of glucocorticoids onepithe lial ce
lls described above, inhaled glucocor-ticoid therapy has be en show
n to reduce the shed-ding of epithe lial cells.1 55 ,15 9,16 0 No
consistent e ffec tof corticosteroids on the thickness of the
basementmembrane has been obse rved.79 ,16 0,161
Besides the suppre ssive e ffec ts on inflammatoryce lls ,
inhaled glucocorticoids have also show n toinhibit mucus secre tion
and mic rovascular leakage (asdete rmined by the dow n-re gulation
of plasma pro-te ins in BAL fluid).1 60 ,16 2 –16 6 At present it
is not clearw hether this is mediated via a dire ct effe ct
ofglucocorticoids on endothe lial or mucous cells, or viaa
reduction of inflammatory mediators that inc re asemucus se cretion
and vascular leakage.
Effects of glucocorticoids on lung function
Treatment w ith glucocorticoids has be en consiste ntlyshow n
not only to re duce the symptoms of as thma,but also bronchial
hyperresponsiveness.13 4,16 7–16 9 Incontrast to the rapid
inhibitory effe cts of b 2-agonis ts,glucocorticoids given in a s
ingle dose are not effe ctivein pre venting early alle rgen-invoked
bronchoconstric-tion, but inhibition of the late re sponse has be
enclearly demonstrated.1 70 ,17 1 In contrast, chronic treat-ment w
ith either oral or inhaled steroids attenuate seven the early
bronchoconstric tion to alle rgen,17 1–17 3
an effe ct that probably is mediated via the anti-inflammatory
actions of glucocorticoids alre adydesc ribed. Although inhaled
glucocorticoids con-sis tently re duce airw ay hyperreac tivity in
asthmat-ics ,16 9 even after several months of treatment re
spon-siveness fails to re turn to the normal range. This mayreflec
t persis tence of structural changes that cannotbe re versed by
steroids (such as the thickening of thebasement membrane ), despite
of suppress ion of theinflammatory and immunologic al
processes.
Concluding RemarksGlucocorticoids are w idely used in the tre
atment ofasthma and have anti-inflammatory e ffec ts. The se
effects are mediated either by direc t binding of
theglucocorticoid/GR complex to GRE in the promoterregion of
respons ive gene s, or by an inte raction of thiscomplex w ith
transcription fac tors such as AP-1 andNF-k B. Glucocorticoids
inhibit the ex pression of alarge number of inflammation-assoc
iated molecules,including cytokines, chemokines, arachidonic ac
idmetabolite s, and adhesion molecules. These e ffec
tspredominantly are mediated via inhibition of NF-k Bactivity. In
contrast, anti-inflammatory mediators,such as NEP and IL-1 receptor
antagonist, often areup-regulated by glucocorticoids. The bene fic
ial e ffec tsof glucocorticoid the rapy in asthma is demonstratedby
in vivo studie s show ing that treatment of as th-matic patients w
ith inhaled glucocorticoids inhibitsthe inflammation of the airw
ays and s imultaneouslyimprove s the ir lung func tion. The se effe
cts may bemediated in part by modulation of epithelial ce
llfunctions, since many studies, both in v itro and inv ivo , have
show n that glucocorticoids are able tomodulate the inflammatory
func tions of bronchialepithe lial ce lls. Further studies on the
mechanism ofaction of glucocorticoids w ill e ventually le ad to
thedeve lopment of drugs w hich spec ifically inhibit thetransc
ription of inflammatory genes w ithout havingne gative side e ffec
ts, and w ill contribute to a moreeffic ient tre atment of
asthmatic patients .
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ACKNOWLEDGEMENTS. I acknow le dge Mr T. M. van Os for preparing
thefigure .
Received 28 April 1998;accepted 7 May 1998
Glu co co rtico id a ctio n in a s th m a
Mediators of Inflammation · Vol 7 · 1998 237
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