Review Skin Pharmacol Physiol 2005;18:103–114 Received: June 1, 2004 DOI: 10.1159/000084907 Accepted after revision: October 19, 2004 Glucocorticoids for Human Skin: New Aspects of the Mechanism of Action a a a b c M. Schäfer-Korting B. Kleuser M. Ahmed H.-D. Höltje H.C. Korting a Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, Berlin , b Pharmazeutische Chemie, Institut für Pharmazie, Heinrich-Heine-Universität, Düsseldorf , c Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-Universität, München , Deutschland Key Words Introduction Glucocorticoids Genomic effects Glucocorticoid receptor Non-genomic effects Cellular signalling Cortisol, the most potent physiologic glucocorticoid, Skin affects almost all physiologic systems of the organism. Cortisol is synthesised and released from the adrenal cor- tex under hypothalamic control in a pulsatile and circa- Abstract dian way. Importantly, under stress the adrenals secrete Topical glucocorticoids have always been considered cortisol on top of this rhythm, which facilitates recovery. fi rst-line drugs for infl ammatory diseases of the skin and In case of immune challenge, cortisol protects the organ- bronchial system. Applied systemically, glucocorticoids ism against damaging infl ammatory responses. Due to are used for severe infl ammatory and immunological the multiple targets of action, cortisol and more impor- diseases and the inhibition of transplant rejection. Ow- tantly synthetic derivatives are fi rst-line drugs in the ing to the progress in molecular pharmacology, the treatment of immunologic and infl ammatory diseases, as knowledge of the mechanism of action has increased for example infl ammatory bowel disease, arthritis and during the last years. Besides distinct genomic targets, systemic lupus erythematosus. Moreover, glucocorticoids which are due to the activation of specifi c cytoplasmatic are effective in the treatment of some neoplastic diseases, receptors resulting in the (trans-) activation or (trans-) e.g. acute lymphatic leukemia of children. repression of target genes, there are non-genomic ef- In many infl ammatory skin diseases [1] as well as in fects on the basis of the interference with membrane-as- persistent bronchial asthma [2] , topical glucocorticoids sociated receptors as well as with membrane lipids. In are a mainstay of therapy, as unwanted effects are less fact, various glucocorticoids appear to differ with respect prominent compared with systemic treatment. With re- to the relative infl uence on these targets. Thus, the ex- spect to the skin, antiproliferative, apoptotic or antiapop- tended knowledge of glucocorticoid-induced cellular totic and also vasoconstrictive effects may contribute to signalling should allow the design and development of the desired anti-infl ammatory and immunosuppressive even more specifi cally acting drugs – as it has been ob- effects, yet may also result in unwanted side effects in tained with other steroids, e.g. estrogens for osteoporo- other diseases. Moreover, it has been learnt that glucocor- sis prevention. ticoids do not only differ with respect to potency but also Copyright © 2005 S. Karger AG, Basel in the benefi t/risk ratio [3] , which is linked to a selective infl uence on cytokine synthesis [4, 5] . While this was fi rst © 2005 S. Karger AG, Basel Prof. Dr. M. Schäfer-Korting 1660–5527/05/0183–0103$22.00/0 Institut für Pharmazie (Pharmakologie und Toxikologie) Fax +41 61 306 12 34 Freie Universität Berlin, Königin-Luise-Strasse 2–4 E-Mail [email protected] Accessible online at: DE–14195 Berlin (Deutschland) www.karger.com www.karger.com/spp Tel. +49 30 838 53283, Fax +49 30 838 54399, E-Mail [email protected] reported concerning topical glucocorticoid use in derma- By inducing cellular adhesion molecules, proinfl am- tology, recently this has also been acknowledged with re- matory cytokines (e.g., TNF , IL-1) increase epidermal spect to asthma therapy [6–10] . The understanding of this chemokine formation and T cell localisation. CCL17 and separation increases since several new aspects of the glu- CCL22, chemokines with two highly conserved adjacent cocorticoid signalling pathways were revealed during the cysteine residues formed by IL-4 and IL-13 stimulation, last years, expanding our knowledge on the mechanism recruit T cells to skin and lung. Keratinocytes from pa- of drug action. Various aspects of glucocorticoid action tients with atopic dermatitis express also other Th attrac- have been reviewed previously emphasising comparison tant chemokines such as RANTES, MCP-1 and – most of glucocorticoids and other immunomodulators [11] , importantly – CCL27 more abundantly [23, 24] . non-genomic glucocorticoid effects [12–14] , cross-talk Most importantly, there is an intense cross-talk of the with cytokines and transcription factors [15–18] , gluco- various signalling pathways described, and maximum ac- corticoid-mediated apoptosis [19] , receptor isoforms [20] tivation of a cell means the activation of more than a but also effects in asthma [9, 21] . Here, we describe the single pathway. Moreover, enzymes from the MAP ki- multifaceted aspects of the mechanism of glucocorticoid nase pathway may also interact with the NF- B cascade action which are currently known and their translation [15, 16] . into the therapy of infl ammatory skin diseases. By inhibiting the formation of infl ammatory cyto- kines, glucocorticoids interfere with the activation of a variety of immunologic cells. Glucocorticoids inhibit the Infl uence on the Cytokine Network activation of dendritic cells which normally stimulate Th2 cells and in the lung also B cells. Moreover, eosino- An imbalance of helper T cells in atopic eczema and phil and T cell apoptosis increases. Yet, glucocorticoids asthma results in an increased baseline mediator forma- also infl uence other cells such as keratinocytes, fi broblasts tion [22] . Consequently, alveolar macrophages of asthma and alveolar cells. Besides genomic effects, non-genomic patients and keratinocytes of patients with atopic derma- targets appear to contribute to glucocorticoid effects. titis release interleukin-1 (IL-1), tumour necrosis factor- (TNF- ) and granulocyte-macrophage colony-stimulat- ing factor (GM-CSF) at an increased rate [21, 23–25] . By Genomic Glucocorticoid Effects stimulating cytokine receptors on the cell surface, IL-1 and TNF- induce a cellular signal cascade which acti- Receptor Structure vates transcription factors such as signal transducers and In general, steroid hormones induce their effects by activators of transduction (STATs) or the nuclear factor binding to intracellular receptors (glucocorticoid recep- B (NF- B) which is released from the complex with its tor, GR or hGR ; mineralocorticoid receptor, MR; pro- inhibitory protein I B . Another relevant pathway of gesterone receptor, PR; androgen receptor, AR; estrogen IL-1 and TNF- is the activation of the mitogen-activat- receptor, ER; fi g. 1 ) which are closely interrelated and ed protein (MAP) kinase, and thus the activation of acti- form a superfamily together with the receptors for thyroid vator protein 1 (AP-1) which also results in the activation hormone, retinoids, vitamin D but also the peroxisome of nuclear factor of activated T cells (NFAT) containing proliferator activated receptor. Today, various isoforms AP-1 as an integral part. AP-1 and NF- B activate re- of these receptors are known. These proteins are charac- sponse genes by binding to their promotor region, recruit- terised by an N-terminal domain activating gene expres- ment of co-activators and basal transcription factors. His- sion, a central DNA-binding moiety and a C-terminal tone acetylation by activated histone acetyl transferases ligand-binding domain. results in a more relaxed chromatin environment which The highly conserved central DNA-binding domain of enables the access of RNA polymerase to the coding re- about 70 residues contains two loops which are stabilised gion of the target gene. These are genes coding for cyto- by four cysteine residues each complexing to zinc ions kines (IL-1, IL-2, IL-4, IL-6, IL-13, TNF- ), chemotaxis (zinc fi ngers). The N-terminal zinc fi nger discriminates proteins (e.g., GM-CSF), cellular adhesion molecules, i.e. between the different response elements and therefore is intercellular adhesion molecule (ICAM-1), vascular cell important for the selectivity of glucocorticoid effects. The adhesion molecule (VCAM-1), but also enzymes, i.e. DNA-binding domain is fl anked by an N-terminal trans- phospholipase A 2 , inducible forms of cyclooxygenase activating moiety ( 1) which after receptor binding en- (COX-2) and NO synthase (iNOS). hances the transcription of target genes. The ligand-bind- 104 Skin Pharmacol Physiol 2005;18:103–114 Schäfer-Korting/Kleuser /Ahmed /Höltje / Korting Fig. 1. Human glucocorticoid receptor gene, mRNA splice variants and receptor pro- teins (hGR and hGR ); modifi ed from [20] . Fig. 2. Glucocorticoid receptor binding as determined experimentally [30, 81] . BM = Betamethasone; BMP = betamethasone di- propionate; BMV = betamethasone 17-val- erate; BU = budesonide; CBP = clobetasol 17-propionate; DEX = dexamethasone; MOM = mometasone; MPD = methylpred- nisolone; PC = prednicarbate; PD = pred- nisolone; TAA = triamcinolone acetonide. ing domain is built up from 12 -helices, the segment 2 acid and arginine of ER which interact with the phenolic of the liganded receptor, which is part of helix 12, favours group of the estrogens [26,