Local cortisol/corticosterone activation in skin physiology and pathology


      Cortisol and corticosterone are the endogenous glucocorticoids (GCs) in humans and rodents, respectively. Systemic GC is released through the hypothalamic-pituitary-adrenal (HPA) axis in response to various stressors. Over the last decade, extra-adrenal production/activation of cortisol/corticosterone has been reported in many tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone/11-dehydrocorticosterone (11-DHC) into active cortisol/corticosterone in cells is 11β-hydroxysteroid dehydrogenase (11β-HSD). The 11β-HSD1 isoform is predominantly a reductase, which catalyzes nicotinamide adenine dinucleotide phosphate hydrogen-dependent conversion of cortisone/11-DHC to cortisol/corticosterone, and is widely expressed and present at the highest levels in the liver, lungs, adipose tissues, ovaries, and central nervous system. The 11β-HSD2 isoform, which catalyzes nicotinamide adenine dinucleotide+-dependent inactivation of cortisol/corticosterone to cortisone/11-DHC, is highly expressed in distal nephrons, the colon, sweat glands, and the placenta. In healthy skin, 11β-HSD1 is expressed in the epidermis and in dermal fibroblasts. On the other hand, 11β-HSD2 is expressed in sweat glands but not in the epidermis. The role of 11β-HSD in skin physiology and pathology has been reported recently. In this review, we summarize the recently reported role of 11β-HSD in the skin, focusing on its function in cell proliferation, wound healing, inflammation, and aging.


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        • Sapolsky R.M.
        • Romero L.M.
        • Munck A.U.
        How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.
        Endocr. Rev. 2000; 21: 55-89
        • Zhou J.
        • Cidlowski J.A.
        The human glucocorticoid receptor: one gene, multiple proteins and diverse responses.
        Steroids. 2005; 70: 407-417
        • Noti M.
        • Corazza N.
        • Mueller C.
        • Berger B.
        • Brunner T.
        TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis.
        J. Exp. Med. 2010; 207: 1057-1066
        • Coste A.
        • Dubuquoy L.
        • Barnouin R.
        • Annicotte J.S.
        • Magnier B.
        • Notti M.
        • et al.
        LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease.
        Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 13098-13103
        • Mueller M.
        • Cima I.
        • Noti M.
        • Fuhrer A.
        • Jakob S.
        • Dubuquoy L.
        • et al.
        The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine.
        J. Exp. Med. 2006; 203: 2057-2062
        • Young M.J.
        • Clyne C.D.
        • Cole T.J.
        • Funder J.W.
        Cardiac steroidogenesis in the normal and failing heart.
        J. Clin. Endocrinol. Metab. 2001; 86: 5121-5126
        • Kayes-Wandover K.M.
        • White P.C.
        Steroidogenic enzyme gene expression in the human heart.
        J. Clin. Endocrinol. Metab. 2000; 85: 2519-2525
        • Ohtani T.
        • Mano T.
        • Hikoso S.
        • Sakata Y.
        • Nishio M.
        • Takeda Y.
        • et al.
        Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the progression to heart failure.
        J. Hypertens. 2009; 27: 1074-1083
        • Hostettler N.
        • Bianchi P.
        • Gennari-Moser C.
        • Kassahn D.
        • Schoonjans K.
        • Corazza N.
        • et al.
        Local glucocorticoid production in the mouse lung is induced by immune cell stimulation.
        Allergy. 2012; 67: 227-234
        • Slominski A.T.
        • Manna P.R.
        • Tuckey R.C.
        On the role of skin in the regulation of local and systemic steroidogenic activities.
        Steroids. 2015; 103: 72-88
        • Slominski A.
        • Gomez-Sanchez C.E.
        • Foecking M.F.
        • Wortsman J.
        Metabolism of progesterone to DOC, corticosterone and 18OHDOC in cultured human melanoma cells.
        FEBS Lett. 1999; 455: 364-366
        • Slominski A.
        • Zbytek B.
        • Szczesniewski A.
        • Semak I.
        • Kaminski J.
        • Sweatman T.
        • et al.
        CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.
        Am. J. Physiol. Endocrinol. Metab. 2005; 288: E701-706
        • Terao M.
        • Murota H.
        • Kimura A.
        • Kato A.
        • Ishikawa A.
        • Igawa K.
        • et al.
        11beta-hydroxysteroid dehydrogenase-1 is a novel regulator of skin homeostasis and a candidate target for promoting tissue repair.
        PLoS One. 2011; 6: e25039
        • Pan T.L.
        • Wang P.W.
        • Aljuffali I.A.
        • Huang C.T.
        • Lee C.W.
        • Fang J.Y.
        The impact of urban particulate pollution on skin barrier function and the subsequent drug absorption.
        J. Dermatol. Sci. 2015; 78: 51-60
        • Son E.D.
        • Kim H.J.
        • Park T.
        • Shin K.
        • Bae I.H.
        • Lim K.M.
        • et al.
        Staphylococcus aureus inhibits terminal differentiation of normal human keratinocytes by stimulating interleukin-6 secretion.
        J. Dermatol. Sci. 2014; 74: 64-71
        • Ito T.
        • Seo N.
        • Yagita H.
        • Tsujimura K.
        • Takigawa M.
        • Tokura Y.
        Alterations of immune functions in barrier disrupted skin by UVB irradiation.
        J. Dermatol. Sci. 2003; 33: 151-159
        • Odermatt A.
        • Atanasov A.G.
        • Balazs Z.
        • Schweizer R.A.
        • Nashev L.G.
        • Schuster D.
        • et al.
        Why is 11beta-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Physiological relevance of the membrane topology of 11beta-HSD1.
        Mol. Cell. Endocrinol. 2006; 248: 15-23
        • Masuzaki H.
        • Paterson J.
        • Shinyama H.
        • Morton N.M.
        • Mullins J.J.
        • Seckl J.R.
        • et al.
        A transgenic model of visceral obesity and the metabolic syndrome.
        Science. 2001; 294: 2166-2170
        • Bryndova J.
        • Zbankova S.
        • Kment M.
        • Pacha J.
        Colitis up-regulates local glucocorticoid activation and down-regulates inactivation in colonic tissue.
        Scand. J. Gastroenterol. 2004; 39: 549-553
        • Chapman K.E.
        • Coutinho A.E.
        • Zhang Z.
        • Kipari T.
        • Savill J.S.
        • Seckl J.R.
        Changing glucocorticoid action: 11beta-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation.
        J. Steroid Biochem. Mol. Biol. 2013; 137: 82-92
        • Gambineri A.
        • Fanelli F.
        • Tomassoni F.
        • Munarini A.
        • Pagotto U.
        • Andrew R.
        • et al.
        Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 in overweight/obese women with polycystic ovary syndrome compared with weight-matched controls.
        Eur. J. Endocrinol. 2014; 171: 47-57
        • Ergang P.
        • Leden P.
        • Vagnerova K.
        • Klusonova P.
        • Miksik I.
        • Jurcovicova J.
        • et al.
        Local metabolism of glucocorticoids and its role in rat adjuvant arthritis.
        Mol. Cell. Endocrinol. 2010; 323: 155-160
        • Choi E.H.
        • Demerjian M.
        • Crumrine D.
        • Brown B.E.
        • Mauro T.
        • Elias P.M.
        • et al.
        Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006; 291: R1657-R1662
        • Sheu H.M.
        • Tai C.L.
        • Kuo K.W.
        • Yu H.S.
        • Chai C.Y.
        Modulation of epidermal terminal differentiation in patients after long-term topical corticosteroids.
        J. Dermatol. 1991; 18: 454-464
        • Zoller N.N.
        • Kippenberger S.
        • Thaci D.
        • Mewes K.
        • Spiegel M.
        • Sattler A.
        • et al.
        Evaluation of beneficial and adverse effects of glucocorticoids on a newly developed full-thickness skin model.
        Toxicol. In Vitro. 2008; 22: 747-759
        • Demerjian M.
        • Choi E.H.
        • Man M.Q.
        • Chang S.
        • Elias P.M.
        • Feingold K.R.
        Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis.
        Exp. Dermatol. 2009; 18: 643-649
        • Rabbitt E.H.
        • Lavery G.G.
        • Walker E.A.
        • Cooper M.S.
        • Stewart P.M.
        • Hewison M.
        Prereceptor regulation of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation.
        FASEB J. 2002; 16: 36-44
        • Terao M.
        • Tani M.
        • Itoi S.
        • Yoshimura T.
        • Hamasaki T.
        • Murota H.
        • et al.
        11beta-hydroxysteroid dehydrogenase 1 specific inhibitor increased dermal collagen content and promotes fibroblast proliferation.
        PLoS One. 2014; 9: e93051
        • Terao M.
        • Itoi S.
        • Murota H.
        • Katayama I.
        Expression profiles of cortisol-inactivating enzyme, 11beta-hydroxysteroid dehydrogenase-2, in human epidermal tumors and its role in keratinocyte proliferation.
        Exp. Dermatol. 2013; 22: 98-101
        • Hubner G.
        • Brauchle M.
        • Smola H.
        • Madlener M.
        • Fassler R.
        • Werner S.
        Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice.
        Cytokine. 1996; 8: 548-556
        • Christian L.M.
        • Graham J.E.
        • Padgett D.A.
        • Glaser R.
        • Kiecolt-Glaser J.K.
        Stress and wound healing.
        Neuroimmunomodulation. 2006; 13: 337-346
        • Tiganescu A.
        • Tahrani A.A.
        • Morgan S.A.
        • Otranto M.
        • Desmouliere A.
        • Abrahams L.
        • et al.
        11beta-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects.
        J. Clin. Invest. 2013; 123: 3051-3060
        • Coleman D.L.
        Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.
        Diabetologia. 1978; 14: 141-148
        • Zhang Y.
        • Proenca R.
        • Maffei M.
        • Barone M.
        • Leopold L.
        • Friedman J.M.
        Positional cloning of the mouse obese gene and its human homologue.
        Nature. 1994; 372: 425-432
        • Koyama K.
        • Myles K.
        • Smith R.
        • Krozowski Z.
        Expression of the 11beta-hydroxysteroid dehydrogenase type II enzyme in breast tumors and modulation of activity and cell growth in PMC42 cells.
        J. Steroid Biochem. Mol. Biol. 2001; 76: 153-159
        • Patel P.
        • Hardy R.
        • Sumathi V.
        • Bartle G.
        • Kindblom L.G.
        • Grimer R.
        • et al.
        Expression of 11beta-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments.
        Endocr. Relat. Cancer. 2012; 19: 589-598
        • Terao M.
        • Itoi S.
        • Matsumura S.
        • Yang L.
        • Murota H.
        • Katayama I.
        Local glucocorticoid activation by 11beta-Hydroxysteroid dehydrogenase 1 in keratinocytes: the role in hapten-induced dermatitis.
        Am. J. Pathol. 2016; 186: 1499-1510
        • Hassan-Smith Z.K.
        • Morgan S.A.
        • Sherlock M.
        • Hughes B.
        • Taylor A.E.
        • Lavery G.G.
        • et al.
        Gender-specific differences in skeletal muscle 11beta-HSD1 expression across healthy aging.
        J. Clin. Endocrinol. Metab. 2015; 100: 2673-2681
        • Cooper M.S.
        Glucocorticoids in bone and joint disease: the good, the bad and the uncertain.
        Clin. Med. 2012; 12: 261-265
        • Yau J.L.
        • Wheelan N.
        • Noble J.
        • Walker B.R.
        • Webster S.P.
        • Kenyon C.J.
        • et al.
        Intrahippocampal glucocorticoids generated by 11beta-HSD1 affect memory in aged mice.
        Neurobiol. Aging. 2015; 36: 334-343
        • Biniek K.
        • Kaczvinsky J.
        • Matts P.
        • Dauskardt R.H.
        Understanding age-induced alterations to the biomechanical barrier function of human stratum corneum.
        J. Dermatol. Sci. 2015; 80: 94-101
        • Xia W.
        • Quan T.
        • Hammerberg C.
        • Voorhees J.J.
        • Fisher G.J.
        A mouse model of skin aging: fragmentation of dermal collagen fibrils and reduced fibroblast spreading due to expression of human matrix metalloproteinase-1.
        J. Dermatol. Sci. 2015; 78: 79-82
        • Tiganescu A.
        • Walker E.A.
        • Hardy R.S.
        • Mayes A.E.
        • Stewart P.M.
        Localization, age- and site-dependent expression, and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in skin.
        J. Invest. Dermatol. 2011; 131: 30-36
        • Nuutinen P.
        • Autio P.
        • Hurskainen T.
        • Oikarinen A.
        Glucocorticoid action on skin collagen: overview on clinical significance and consequences.
        J. Eur. Acad. Dermatol. Venereol. 2001; 15: 361-362
        • Oishi Y.
        • Fu Z.W.
        • Ohnuki Y.
        • Kato H.
        • Noguchi T.
        Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: effects on the synthesis of collagen type I and III, collagenase, and tissue inhibitors of metalloproteinases.
        Br. J. Dermatol. 2002; 147: 859-868
        • Lehmann P.
        • Zheng P.
        • Lavker R.M.
        • Kligman A.M.
        Corticosteroid atrophy in human skin. A study by light, scanning, and transmission electron microscopy.
        J. Invest. Dermatol. 1983; 81: 169-176
        • Ishii T.
        • Masuzaki H.
        • Tanaka T.
        • Arai N.
        • Yasue S.
        • Kobayashi N.
        • et al.
        Augmentation of 11beta-hydroxysteroid dehydrogenase type 1 in LPS-activated J774. 1 macrophages-role of 11beta-HSD1 in pro-inflammatory properties in macrophages.
        FEBS Lett. 2007; 581: 349-354
        • Skobowiat C.
        • Sayre R.M.
        • Dowdy J.C.
        • Slominski A.T.
        Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo.
        Br. J. Dermatol. 2013; 168: 595-601
        • Itoi-Ochi S.
        • Terao M.
        • Murota H.
        • Katayama I.
        Local corticosterone activation by 11beta-hydroxysteroid dehydrogenase 1 in keratinocytes: the role in narrow-band UVB-induced dermatitis.
        Dermato-endocrinology. 1995; 18: 2016
        • Tiganescu A.
        • Hupe M.
        • Jiang Y.J.
        • Celli A.
        • Uchida Y.
        • Mauro T.M.
        • et al.
        UVB induces epidermal 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo.
        Exp. Dermatol. 2015; 24: 370-376


      Mika Terao (M.D., Ph.D.) is Assistant Professor at Department of Regenerative Dermatology, Osaka University School of Medicine, Osaka, Japan. She received her MD degree from University of Tsukuba, Japan and her Ph.D. degree from Osaka University, Japan. She served several months of externship in University of Irvine, CA, USA. She has particular interest in dermatoendocrinology especially in the role of cortisol and vitamin D in the skin. She started to have an interest in local cortisol/corticosterone activating enzyme when she was Ph.D. student. Since then, she has generated knockout mice and investigating the role of this enzyme in vivo and the role in human skin diseases.