Review

Mediators of Inflammation, 7 , 229237 (1998)

GLUCOCORTIC OIDS ar e p o te nt in h ibitors o f in flam m atory p r oces s e s and are w ide ly use d in th e tre atm en t of as th m a. Th e an ti-inflam m ato ry effe cts are m e diated eith er by dire ct bin din g of th e gluco co rticoid/gluco cortico id r ecep tor co m p lex to glucocortico id r es po ns ive e lem e nts in th e p r om oter r e gion of ge ne s , o r by an in te raction of th is com p lex w ith oth e r tran s cription factors , in p articular activatin g p ro te in -1 o r n uclear fa ctor -k B. Gluco co rticoids in h ib it m an y in flam m atio n-as s o cia te d m ole cules s uch as cyto kin es , ch em o kin es , arach idon ic acid m etabolites , and adh e s ion m o lecules . In co ntras t, an ti-inflam m ato ry m ediators ofte n are up -r e gulate d by glucocortico ids . In vivo s tudie s h ave s h o w n th at tr eatm e nt of as th m atic p atie nts w ith in h aled gluco co rticoids in h ibits th e br on ch ial in flam m ation an d s im ultan eous ly im p r oves th eir lun g function . In th is r evie w , our curr en t kn ow le dge of th e m ech an is m of action of glucocor ticoids an d th eir anti-in flam m atory p oten tial in as th m a is des cribe d. Sin ce br on ch ial ep ith e lial cells m ay be im p ortan t tar ge ts for gluco co rticoid th e rap y in as th m a, th e effects of glucocor ticoids on ep ith e lial e x p re s s ed in flam m ato ry ge n es w ill be em p h as ize d. Key w o r ds : Glucocorticoids, Asthma, Bronchial epithe lial ce lls, Inflammation

Glucocorticoids: mechanisms of action and anti-inflammatory potential 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 7192 Fax : (+31) 10 436 7601 Email: vandervelden@immu.fgg.eur.nl

Introduction
Glucocortic oids are hormones synthe size d in the adrenal cortex and sec re te d into the blood, w here the levels of gluc oc ortic oids fluctuate in a circadian mode . In humans, the naturally occ urring gluc ocortic oid is hydroc ortisone (c ortisol), w hich is synthesized from its pre c ursor cortisone . The be ne ficial e ffec ts of glucocorticoids in as thmatic patients w ere first de scribe d in 1950.1 Sinc e then on, many studie s have foc used on the therapeutic pote ntial of glucocortic oids. Several synthetic gluc ocorticoids, much more potent than c ortisol and w ithout the unw ante d mine ralocorticoid side e ffec ts, have be en developed. Now adays, glucocorticoids are pow e rful agents in the tre atment of inflammatory diseases and are by far the most effective antiinflammatory drugs used in the treatment of asthma.

Glucocorticoid receptor
To ex ert the ir effe cts, gluc oc ortic oids ne ed to bind to a spec ific cytoplasmic glucocortic oid re ce ptor (GR). Almost all ce lls of the body ex pre ss the GR, but the number of re cep tors may vary be tw een differe nt ce ll type s.2 Cloning of the GR has re veale d that the GR cons is ts of approx imately 800 amino ac id re sidues, and that ce rtain areas of the mole cule show homology w ith othe r ste roid re ce ptors, re c eptors for thyroid hormones, and re ce ptors for re tinoic acid.3 7 All me mbers of the nuclear hormone re c eptor family share a charac te ristic thre e-domain structure , first desc ribed for the human GR. The C-te rminal domain is equal in size in all nucle ar re c eptors studied (about 250 amino ac ids) and its main function is to bind the ste roid. 8 It also c ontain s the binding site s for the heat shock prote ins (hsp) 90.9,1 0 Removal of the ste roidbinding domain re sults in a c onstitutiv ely ac tive GR molecule, indicating that this part of the mole cule acts as a re pre ssor of the transcription-activation function. The most c onserve d ce ntral domain is involved in direct binding of the re ce ptor to DNA. It contains tw o distinct loop s of prote in, each bound at their base via four cyste ine re sidue s to a single zinc ion, the so-c alled zinc fingers.1 1 These zinc cluste rs are involved in binding of the GR to the major groove of the DNA double he lix and play a role in dimeriza229

Mechanism of Action
Although gluc oc orticoids have be en know n for a long period of time , the ir pre c ise mechanism of ac tion is still not complete ly unde rstood. How e ver, re ce nt studies have inc re ased our understanding of their complex me chanisms of action.
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V. H. J. va n de r Ve lde n

tion of tw o GR molec ule s.1 2,1 3 In addition, the central DNA-binding domain has a transcription-activation func tion. 4 ,14 The ste roid-bindin g and DNA-binding domains are separate d by the hinge-re gion, w hich contains se que nce s that are important for nucle ar translocation and dimerization. 9,10 The N-te rminal domain is ex treme ly variable in size (24600 amino acids). Its pre cis e role is still unc ertain, but it is re quired in transc riptional activation. 15 Tw o differe nt forms of the human GR have be en desc ribe d.3 ,1 6 The se tw o highly homologous is oforms, te rmed GRa and GRb , are gene rate d by alternativ e splic ing of the human GR pre -mRNA. The GRb isoform diffe rs from the GRa isoform only in its C-te rminal domain, in w hich the last 50 amino acids of the latte r are re plac ed by a unique 15 amino ac id se que nce . How ever, this re plac eme nt has dramatic functional cons eque nce s, sinc e the GRb isoform is unable to bind gluc oc ortic oids and to transduc e ligand-depende nt transac tivation. How e ve r, the physiological signific anc e of the GRb isoform re mains questionable, since some re c ent studies indic ate that this form is not conse rved among spec ie s and no dominant ne gative inhibition of GRa activity c ould be found. 17 ,1 8 Ne vertheless, abundant ex p re ssion of GRb prote in c an be found in the epithe lial cells lining the te rminal bronchioli of the lung.19 The ex pre ssion of the GR may be re gulated by numerous fac tors either at the transc riptional, translational or p ost-translational le ve l.2 0,21 Glucoc ortic oids have be en show n to dow n-re gulate the ex pre ssion of the GR, both in v itro and in vivo .22 ,23 In contrast, inflammatory me diators like interle ukin (IL)-1b , IL-4, tumour ne crosis fac tor (TNF)-a , lipopolysac charide (LPS) and interferon (IFN)-g have be e n show n to inc re as e gluc oc ortic oid binding in vitro .24 28 How e ve r, the inc re ase in GR numbe rs may be ac companied by a re duc ed affinity for glucocortic oids.24 ,2 8 Analysis of GR localization in normal and asthmatic lung has not re vealed differe nc es in the le vel or sites of GR ex p re ssion. 2 9

FIG. 1. Schematic representation of the cellular events after administration of glucocorticoids (adapted from Ref. 39).

Furthe rmore , in the nucle us ligande d GR form homodime rs (Fig. 1). Within the nucleus, the GR homodimers may re gulate ge ne transc ription in se ve ral w ays: (1) via binding of the gluc oc ortic oid-GR c omplex to spec ific DNA se quenc es, the re by directly ac tivating or re pre ssing gene s; (2) via inte raction w ith other transcription factors; and (3) via modulating the stability of specific mRNA molec ule s.3 5 3 9 Bin ding to DNA s e qu e n c e s Se ve ral ste roid-re sponsive ge ne s contain glucocortic oid re sponsive ele ments (GRE) in their promoter re gion. 3 5,4 0 Binding of GR homodime rs to GRE may either re sult in transcriptional activation of the ge ne (via a p o s itive GRE) or re pre ssion of the gene (via a n e g a tive GRE) (Fig. 1). The cons ensus sequenc e for (positive) GRE is the palindromic 15-base-pair se que nce GGTACAnnnTGTTCT, w here as the ne gative GRE has a more variable sequenc e.36 The rate of transc riptional re gulation of ste roid-re sponsive gene s is de pendent on both the numbe rs of GRE, the affinity of the glucocortic oid-GR complex to the GRE, and the position of the GRE re lative to the transcriptional start site. Binding of the complex to GRE may re sult in conformationa l change s in the DNA and ex posure of pre viously maske d areas, re sulting in incre ase d binding of othe r transcription factors.4 1 44 In te ra c tio n w ith o th e r tra n s c riptio n fa c to rs Many ste roid-re sp onsive gene s do not have GRE in their promoter re gion. How ever, binding site s for othe r transcription factors, including nuclear factor (NF)-k B, ac tivating prote in (AP)-1, and cAMP-re sponsive eleme nt binding protein (CREB), often c an be found. 45

Regulation of gene transcription

In the abse nce of glucocorticoids, the GR is pre se nt in the c ytoplasm of the c ell as a he te ro-oligomer cons is ting of the GR itself, tw o mole cule s of hsp 90, one mole cule hsp 70, and one molec ule of hsp 56 (w hich p robably does not interact w ith the GR itself, but interacts w ith hsp 90).30 3 4 Glucocortic oids enter the cytoplasm of the ce ll by passive diffusion through the c ell me mbrane. In the cytoplasm the y bind to the GR c omplex , w hich subsequently undergoes c onformational change s, re sulting in the dissoc iation of the hsp 90 and hsp 56 molecules. Upon this activation, the gluc oc orticoidGR complex passe s the nuc le ar membrane, enters the nuc le us, and the hsp 70 mole cule is dissoc iate d.
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AP-1, w hich is a dimer of tw o proto-oncogene s (membe rs of the c-jun and c-fos family),46 ,47 is involved in the re gulation of se veral ge ne s, including adhesion molecules and cytokines (re view ed in Ref. 47). Dire ct protein prote in inte raction be tw ee n AP-1 and the glucocortic oid-GR c omplex re sults in re c iprocal re pre ssion of one anothers transc riptional activation by pre ve nting binding of the AP-1 and gluc ocortic oid-GR c omplex to AP-1 sites and GRE, re spective ly (Fig. 1).3 7,4 8,4 9 Comparable to AP-1, NF-k B (a hete rodimer of p50 and p65 subunits 5 0,51 ) re gulate s the transcription of se veral gene s involve d in inflammatory re actions.5 0,52,5 3 In unstimulated ce lls, NF-k B is re tained in the c ytoplasm of the cells through the interaction w ith the inhibitor s Ik Ba and Ik Bb .5 4 56 Upon c ell stimulation, for ex ample by IL-1 b or TNF-a , Ik B are rap idly phosp horylated, ubiquitinated, and consequently prote olysed.53 ,57 The liberated NF-k B dimers translocate to the nucleus w he re the y can ac tivate target gene s. Glucocortic oids may inhibit NF-k B-stimulated gene s by a direct interaction be tw e en the glucoc ortic oid-GR complex and the p65 subunit of NF-k B, re sulting in transre pre ssion (Fig. 1).5 1,5 5,5 8,5 9 Furthe rmore , glucocortic oids may indirec tly antagonize NF-k B me diate d transc ription by up-re gulating the synthesis of the inhibitory protein Ik Ba , w hich trap s NF-k B in inac tive cytoplasmic complex e s.39 ,54 ,5 5 A large numbe r of immunore gulatory ge ne s, w hose ex p re ssion is induc ed by a variety of pro-inflammatory me diators, contain NF-k B sites in their promote rs/re gulatory re gions. The re fore , it is no w onde r that gluc oc ortic oids have be en found to pre ve nt the ex p re ssion of the se gene s, including those coding for IL-1 b , IL-2, IL-6, IL-8, monocyte chemoattrac tant prote in (MCP)-1, RANTES (Regulated up on Activation, Normal T ce ll Ex pre sse d, and pre sumably Sec re te d), granulocyte mac rop hage colony-stimulating factor (GM-CSF), the IL-2 re c eptor, inte rcellular adhe sion molec ule (ICAM)-1, and E-se le ctin (re view ed in Ref. 45). Probably, interactions be tw e en glucocortic oids and NF-k B or AP-1 w ill ex plain most of the anti-inflammatory and immunosuppre ssive activities of glucocortic oids. An inte rac tion be tw ee n CREB and the glucocortic oid-GR c omplex has also be e n sugge ste d.6 0,6 1 b -agonists, w hich are used as bronchodilators in the tre atment of asthma, inc re ase c AMP formation and subse que ntly ac tivate CREB. The re fore , simultaneous tre atment of as thmatic patients w ith gluc oc ortic oids and b -agonists may re sult in re duced re sponsivene ss of the airw ays for ste roids.6 1 63 Mo du la tio n o f m RNA s ta bility. A third me chanism by w hich glucocortic oids may re gulate the synthesis of p rote ins is via enhance d transc ription of spec ific ribonuclease s w hich are able to degrade mRNA c ontainin g constitutiv e AU-rich se que nce s in the untranslated 3 9 -re gion. 64 Such gluco-

Table 1. Influence of glucocorticoids on the synthesis of proteins with inflammatory effects by bronchial epithelial cells Protein Cytokines IL-1b , IL-6, IL-11, TNF-a , GM-CSF IL-10, LIF G-CSF Glucocorticoid effect

? =

Chemokines MCP-1, eotaxin, IL-8, RANTES, MIP-1a Receptors NK, GR IL-1R II, IL-6R, b 2-adrenergic receptor Enzymes iNOS, COX-2, cPLA2 NEP Adhesion molecules ICAM-1 Inhibitory proteins Lc-1 IL-1RA type I, SPLI

=/

cortic oid-mediated modulation of post-translational e ve nts (resulting in de cre ased mRNA stability and re duced half-life time) has be en observe d for IL-1 b , IL6 and GM-CSF .6 5,6 6

Glucocorticoid Regulated Genes

Glucocortic oids are able to modulate the transcription of a varie ty of gene s, including cytokines and che mokines, re ce ptors, enzymes, adhesion molecules, and inhibitory prote ins (Table 1). Sinc e epithelial c ells may be one of the most important targets for gluc ocorticoid the rap y in asthma, the effe cts of gluc ocorticoids on epithe lial ex pre ssed inflammatory gene s w ill be emphas ized in this re view.

Cytokines and chemokines

Glucocortic oids inhibit the transcription of most cytokines and che mokines that are re le vant in asthma, including IL-1 b , TNF-a , GM-CSF, IL-3, IL-4, IL-5, IL-6, IL8, IL-11, IL-12, IL-13, RANTES, e otax in, and mac rophage inhibitory prote in (MIP)-1 a .45 ,66 In ge ne ral, re duced synthe sis of these me diators may re sult in a decre as ed re cruitment and ac tivation of le ukocytes, also indire ctly due to e ffec ts on adhe sion molec ule s and c ell survival. Since many cytokine ge ne promote rs do not contain a ne gative GRE, the effects of gluc ocorticoids on cytokine and che mokine production are probably mediated via an e ffec t on a critic al transc ription factor (e spec ially NF-k B and AP-1).6 7 Cross-signalling be tw ee n NF-k B and AP-1 w ith gluc ocortic oid/GR complex have indeed be en demonstrate d in bronchial ep ithe lial cells.6 7
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Bronchial e pithelial cells are c apable of producing a varie ty of c ytokine s and che mokine s that may contrib ute to the initiation and pe rpetuation of airw ay inflammation. Several studies have show n that cytokine-induced ex pre ssion of eotax in, IL-6, IL-8, GMCSF , and RANTES can be diminishe d by glucocortic oids in v itro .68 76 In contrast, glucoc ortic oids did not modulate the sec re tion of G-CSF by human bronchial epithelial cells.7 6 In v ivo studie s have show n that treatme nt w ith inhaled ste roids decre ase s both the ex pre ssion of GM-CSF,77 IL-1 b ,78 IL-8, 79 and RANTES80 by the bronchial ep ithe lium, toge the r w ith the number of ac tivated eosinophils in the epithe lium.

Receptors
Glucocortic oids may modulate the ex pre ssion of se veral re ce ptors. The ex pre ssion of the ne urokinin (NK) 1 re cep tor, w hich me diate s many effects of substanc e P (SP) in the airw ays and is be lieved to be up-re gulate d in asthma,8 1 is dow n-re gulated by glucocortic oids.8 2 Sinc e the NK 1 re ce ptor gene promoter re gion has no GRE but has an AP-1 re sponse eleme nt, this e ffec t probably w ill be me diated via an inte raction of the gluc oc orticoid-GR c omplex w ith AP-1. In c ontrast to NK1 re ce ptors, ex pre ssion of the b 2 -adrene rgic re c eptor is incre ase d by glucocortic oids.8 3 Sinc e the human b 2 -adrene rgic re c eptor gene c ontains thre e potential GRE, this effect of gluc ocorticoids probably is a dire ct one .83 Up-re gulation of b 2 -adrene rgic re ce ptors by gluc oc ortic oids may be re le vant in as thma as it may pre vent dow nre gulation in re sponse to p rolonged tre atment w ith b 2 -agonists .84 The IL-1 re c eptor typ e II, w hich func tions as a decoy re ce ptor,8 5 may also be up-re gulated by gluc ocortic oids, there by re ducing the functional ac tivity of IL-1 agonists.8 6,8 7 Soluble TNF-re ce ptor type I (p 55) re lease by human bronchial epithelial c ells, both cons titutiv e as w ell as IL-1 b -induce d, has be e n show n to be re duce d by gluc oc orticoids.8 8 In contrast, gluc ocorticoids up-re gulate the ex pre ssion of IL-6 re c eptors in rat hep atoma and human epithelial ce lls.89 ,90 Thus far little is know n about this proce ss in human bronchial e pithe lial ce lls, w hich cons titutiv ely ex pre ss these re ce ptors.91 Gluc oc orticoids also modulate the ex pre ssion of their ow n re c eptor. In a re cent study it w as show n that ex pre ssion of the a -form (but not the b -form) of the GR in human bronchial ep ithe lial ce lls w as dow nre gulated in he althy subjects after 4 w e eks of budesonide inhalation .2 3

sis of asthma through an inhibitory effect on enzyme induc tion. The synthe sis of inducible nitric ox ide synthase (iNOS) by human airw ay e pithelial cells is inhibited by glucocortic oids, both in vitro and in v ivo .92 9 4 This effe ct seems to be mediated via inactivation of NF-k B.9 5,9 6 Since nitric ox ide (NO) may contribute to skew ing of Th lymphocytes tow ards a Th2 p henotype , there by promoting IgE production and eosinophil re c ruitment, inhibition of iNOS may be of importanc e in anti-inflammatory therapy in as thma.9 7 Gluc oc orticoids also inhibit the gene transcription of a cytosolic form of phospholipase A2 induc e d by cytokine s 98 and inhibit the gene ex p re ssion of cycloox ygenase-2, re sulting in re duc ed formation of prostaglandins and thrombox anes.99 In contrast to the enzymes me ntione d above, gluc ocorticoids have be en show n to incre ase the ex pre ssion of ne utral e ndope ptidase (NEP),10 0 10 2 there by pote ntially limiting ne urogenic inflammatory re spons es.1 03 In ac cordanc e w ith the se re sults, it w as found that the ex pre ssion of NEP on bronchial epithe lial c ells w as higher in as thmatic s treate d w ith ste roids c ompared w ith nonste roid-treate d asthmatics.1 04

Endothelins
Endothelins are a family of highly homologous 21-amino acid pe ptide s, charac te rized by tw o intrachain disulphide chains, a hairpin loop cons isting of polar amino acids, and a hydrophobic C-te rminal chain. 10 5 Human bronchial epithelial c ells have be en show n to produce ET-1, 1 06 1 08 w hich promotes the prolife ration of smooth muscle ce lls, is a pote nt cons trictor of both vasc ular and non-vascular smooth muscle ce lls, inc re ases the se cre tion of mucus, and may ac tivate inflammatory ce lls.1 05 ,1 07 ,1 0 9 ET-1 also stimulates c ollagen ge ne ex pre ssion and through its inhibitory ac tions on collage nase w ill promote airw ay w all c ollagen deposition, there by contributin g to airw ay w all thickening w hich unde rlies bronchial hyperresp onsive ne ss.11 0 11 2 Inc re as ed le vels of ET1-immunore ac tivity w e re dete cte d in airw ay epithelium and vasc ular e ndothelium of bronchial biopsy spe cime ns from nonste roid-tre ate d asthmatic s compared w ith healthy subje cts .10 6,1 13 ,1 1 4 In c ontrast, no inc re as ed ET-1 ex pre ssion w as found in the bronchial epithe lium of asthmatic patients treate d w ith gluc ocorticoids.11 5

Adhesion molecules
Adhesion mole cules play an imp ortant role in the re c ruitment of inflammatory ce lls to the inflammatory loc us. Ex pre ssion of adhesion mole cule s on endothelial, epithelial or inflammatory ce lls is often

Enzymes
Glucocortic oids inhibit the synthe sis of se veral inflammatory me diators implicate d in the pathoge ne 232 Mediators of Inflammation Vol 7 1998

Glu co co rtico id a ctio n in a s th m a

induc ed by cytokine s, w here as gluc oc ortic oids re duce surfac e ex pre ssion of adhe sion mole cules. This effect may be due either to inhibition of cytokine synthesis or to a direc t effect of gluc oc orticoids on adhesion mole cule gene transcription. It has be en show n that the ex pre ssion of ICAM-1, e ndothelial leukoc yte adhesion molec ule (ELAM)-1, and E-selec tin is dow n-re gulated by ste roids.11 6 Basal and cytokinestimulated ICAM-1 ex pre ssion on human bronchial epithe lial c ell lines is inhibited by glucocortic oids.1 17 ,11 8 How e ve r, inhale d gluc oc orticoids did not modulate ICAM-1 ex p re ssion by bronchial epithelial ce lls from asthmatic s in vivo .11 9 Eosinophil adhe sion to cytokine-stimulated bronchial ep ithe lial c ells w as show n to be inhibited by the synthetic gluc oc orticoid dex ame thasone .120 Although cytokine-activate d epithelial c ells show ed incre ase d ex pre ssion of ICAM-1, this mole cule did not seem to be involved in the dec re ased adhe sion of e osinophils observe d in the pre senc e of dex ame thasone .12 0

Cellular and Clinical Effects of Glucocorticoids in Asthma

Se ve ral studie s have dete rmine d the effe cts of inhale d gluc ocorticoids on bronchial inflammation, e ithe r by me asurements in BAL fluid, sp utum, or ex haled air, or by performing bronchial biopsie s. Although differenc es can be observe d be tw e en differe nt trials, the se studies have confirmed that glucocortic oid treatme nt of asthmatic patients re duces the number and activation of inflammatory ce lls in the airw ays, together w ith an improvement of lung func tion. Now adays, the potent anti-inflammatory ac tions of glucocortic oids are thought to underlie the clinic al e ffic ac y of oral glucoc ortic oids.1 29

Effects of glucocorticoids on immunopathology

Inhaled glucocorticoids de cre ase the numbe r and activation status of most inflammatory c ells in the bronchus, including mast cells, de ndritic ce lls, eosinophils, and T lymphoc ytes. Changes in c ellular infiltration are ac companied by modulate d ex pre ssion of se veral c ytokines. Inhaled gluc oc ortic oids have be en show n to de cre ase mRNA ex p re ssion of GM-CSF, IL13, IL-4, and IL-5, w here as mRNA le vels of IL-12 and IFN-g inc re ased, sugge sting a shift from a Th2tow ards a more Th1-like e nvironment.77 ,13 0,1 31 Gluc oc orticoid tre atment is as sociated w ith a re duction in m a s t c e ll numbe rs in the bronchus 7 9,1 29 ,1 32 13 5 and w ith re duce d mast ce ll associate d mediators in BAL fluid.13 5,1 36 This may be due to a re duc tion in IL-3 and ste m ce ll factor p roduction, w hich are ne c essary for the survival of mast c ells in tissue. The (IgE-depe ndent) re lease of me diators from mast cells does not se em to be affec te d by gluc ocortic oid treatme nt.1 37,13 8 Dendritic cells play an important role in pre se nting antigens to (naive) T ce lls.139 ,1 40 Inhaled gluc ocortic oids have be e n show n to re duce the number of de ndritic c ells in the human bronchial epithe lium.1 41 Incre ase d numbers of e osinophils are a promine nt feature of asthmatic airw ays.14 2 148 In v itro studie s have show n that many eosinophil functions, including adhe re nc e and chemotax is, are diminished follow ing gluc oc ortic oid treatme nt.1 38 How ever, most data suggest that e osinop hil re sponses to ste roids are likely to be indire ct, since e osinop hil func tion is marke dly affec te d by c ytokine s elaborate d from T lymphocytes (IL-3, IL-4, IL-5, GM-CSF), e ndothelial c ells (GM-CSF) and epithelial c ells (GM-CSF).1 49 1 53 In vivo studie s indicate that tre atment w ith inhaled ste roids re duc es the number of eosinophils and eosinophil-re late d me diators in BAL fluid 79 ,1 48,15 4 and the numbe r of (activate d) eosinophils in bronchial biopsie s.79 ,1 29 ,1 3 2,1 33 ,1 55 Rece ntly, induce d sputum has be e n sugge ste d as a useful tool for e valuating the
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Inhibitory proteins
The anti-inflammatory e ffec ts of glucocorticoids may be mediated by incre asing the produc tion of inhibitory prote ins, such as lipocortins. Lip oc ortins are me mbers of a supe rfamily of proteins characte rize d by the ir ability to bind calcium and anionic phospholipids, now know n as the annex ins.12 1,12 2 In se veral ce ll type s, but not all, gluc ocorticoids are induc ers of lipoc ortins, w hich have an inhibitory effec t on the activity of phospholipase A2 .123 ,1 24 As a re sult, the synthesis of lipid me diators, including p rostaglandins and e icosanoids, w ill be re duce d. How ever, in human bronchial e pithelial c ells gluc oc orticoids do not se em to up-re gulate the ex p re ssion of lip oc ortins.12 5 Furthermore , no significant differe nc e w as found be tw e en lipoc ortin-1 c onc entration in BAL fluid from asthmatic patients re ce iving inhale d gluc ocorticoid therapy and those w ho w e re not treate d w ith gluc ocorticoids.12 6 Re ce ntly, glucocorticoids have also be en show n to inc re as e the ex pre ssion of intra cellular IL-1 re c eptor antagonist type I by human bronchial epithelial c ells in vitro .1 27 Incre ase d production of this me diator may inhibit the effe cts of IL-1 agonists , the re by re ducing inflammation. How e ve r, gluc oc orticoid tre atment of asthmatic patients did not affe ct the ex pre ssion of IL-1 re c eptor antagonist by the bronchial e pithe lium.78 To provide prote ction against potentially injurious agents, airw ay e pithe lial cells se cre te a numbe r of me diators, including antiprote ase s. Se cre tory leukocyte prote ase inhibitor (SLPI) is the p re dominant antiprote ase in the airw ays. Its ex pre ssion has be en show n to be inc re ased in airw ay epithelial ce lls after stimulation w ith glucocorticoids.12 8

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effects of the rap y on airw ay muc osal inflammation. Thus far, most studie s have focuse d on the pre senc e of eosinophils and e osinophil-re late d mediators. In accordanc e w ith the findings in BAL fluid and bronchial biopsie s, gluc oc ortic oid treatment w as associated w ith a re duction in sputum eosinophil numbers , eosinophil cationic protein (ECP), and eosinophil pe rox idase (EPO).156 Gluc oc orticoids also re duc e the numbe r of activated T lymphocyte s in bronchial biopsie s and BAL fluid. 1 29 ,1 3 3,1 34 ,1 55,1 5 7 In addition, inhaled cortic oste roids re duc ed the number of ce lls ex pre ssing mRNA for IL-4 or IL-5, and incre ase d the numbe r of cells ex pre ssing mRNA for IFN-g ,1 31 ,13 2 the re by favouring the development of Th1 c ells.15 8 In addition to the e ffec ts of glucocorticoids on epithe lial ce lls described above, inhale d glucocortic oid therapy has be en show n to re duce the she dding of e pithe lial cells.1 55 ,1 5 9,1 6 0 No consiste nt e ffec t of cortic oste roids on the thickness of the baseme nt me mbrane has be en obse rved.79 ,16 0,161 Be sides the sup pre ssive e ffec ts on inflammatory ce lls, inhale d gluc oc ortic oids have also show n to inhibit mucus secre tion and mic rovascular leakage (as dete rmined by the dow n-re gulation of plasma p rote ins in BAL fluid).1 60 ,1 6 2 16 6 At pre sent it is not clear w hether this is me diated via a dire ct effe ct of gluc ocorticoids on endothe lial or mucous c ells, or via a re duction of inflammatory mediators that inc re as e mucus se cre tion and vasc ular leakage.

effects are mediated either by direc t binding of the gluc ocorticoid/GR c omplex to GRE in the promoter re gion of re spons ive gene s, or by an inte raction of this complex w ith transcription fac tors such as AP-1 and NF-k B. Glucocortic oids inhibit the ex pre ssion of a large number of inflammation-assoc iated mole cules, including cytokines, che mokines, arachidonic ac id me tabolite s, and adhesion mole cules. These e ffec ts pre dominantly are me diate d via inhibition of NF-k B activity. In contrast, anti-inflammatory me diators, such as NEP and IL-1 re c eptor antagon ist, often are up-re gulate d by glucocorticoids. The be ne fic ial e ffec ts of glucocorticoid the rap y in asthma is demonstrate d by in vivo studie s show ing that treatme nt of as thmatic patients w ith inhale d glucocorticoids inhibits the inflammation of the airw ays and simultane ously improve s the ir lung func tion. The se effe cts may be me diated in part by modulation of epithelial ce ll functions, sinc e many studies, both in v itro and in v ivo , have show n that glucocortic oids are able to modulate the inflammatory func tions of bronchial epithe lial ce lls. Further studies on the mechanism of action of gluc oc ortic oids w ill e ventually le ad to the development of drugs w hich spec ifically inhibit the transc ription of inflammatory ge ne s w ithout having ne gative side e ffec ts, and w ill contribute to a more effic ie nt tre atment of asthmatic p atie nts.

References
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Effects of glucocorticoids on lung function

Tre atme nt w ith glucocorticoids has be en c onsiste ntly show n not only to re duce the symptoms of as thma, but also bronchial hyperresponsive ne ss.13 4,1 6 7 16 9 In contrast to the rapid inhibitory effe cts of b 2 -agonis ts, gluc ocorticoids given in a single dose are not effe ctive in pre venting early alle rgen-invoke d bronchocons triction, but inhibition of the late re sponse has be en clearly demonstrate d.1 70 ,17 1 In contrast, chronic treatme nt w ith either oral or inhale d ste roids atte nuate s e ve n the early bronchoconstric tion to alle rge n, 17 1 17 3 an effe ct that probably is mediated via the antiinflammatory actions of glucoc ortic oids alre ady desc ribed. Although inhale d glucocorticoids consis te ntly re duce airw ay hyperre ac tivity in asthmatics,16 9 even after se veral months of treatment re sponsivene ss fails to re turn to the normal range. This may re flec t persis te nc e of structural changes that cannot be re verse d by ste roids (such as the thickening of the baseme nt membrane ), despite of suppre ssion of the inflammatory and immunologic al proc esses.

Concluding Remarks
Glucocortic oids are w idely use d in the tre atment of asthma and have anti-inflammatory e ffec ts. The se
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ACKNOWLEDGEMENTS. I acknow le dge Mr T. M. van Os for p rep aring the figure .

Received 28 April 1998; accepted 7 May 1998

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