Abstract:

Human skin expresses elements of the hypothalamo-pituitary-adrenal (HPA) axis including pro-opiomelanocortin (POMC), corticotropin releasing hormone (CRH), the CRH receptor-1 (CRH-R1), key enzymes of corticosteroid synthesis and synthesizes glucocorticoids. Expression of these elements is organized in functional, cell type-specific regulatory loops, which imitate the signaling hierarchy of the HPA axis. In melanocytes and fibroblasts CRH-induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway(s). Melanocytes respond with enhanced production of cortisol and corticosterone, which is dependent on POMC activity. Fibroblasts respond to CRH and ACTH with enhanced production of corticosterone, but not cortisol, which is produced constitutively. Organ-cultured human scalp hair follicles also show a fully functional HPA axis equivalent, including cortisol synthesis and secretion and negative feedback regulation by cortisol on CRH expression. Thus, differential, CRH-driven responses of defined cutaneous cell populations reproduce key features of the central HPA axis at the tissue/single cell levels.

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DIFFERENTIAL EXPRESSION OF HPA AXIS HOMOLOG IN THE SKIN

^{Department of Pathology and Laboratory Medicine, University of Tennessee, HSC, Memphis, TN 38163, USA}

^{Department of Medicine, Southern Illinois University, Springfield, IL, USA}

^{Department of Biochemistry and Molecular Biology, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley WA 6009, Australia}

^{Dept. of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, D-23538 Lübeck, Germany}

Corresponding Author: Andrzej Slominski, MD, PhD; 930 Madison Avenue, Room 525, Memphis, TN 38103; Tel. 901-448-3741; Fax; 901-448-6979; E-mail: ude.memtu@iksnimolsa

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Summary

Human skin expresses elements of the hypothalamo-pituitary-adrenal (HPA) axis including pro-opiomelanocortin (POMC), corticotropin releasing hormone (CRH), the CRH receptor-1 (CRH-R1), key enzymes of corticosteroid synthesis and synthesizes glucocorticoids. Expression of these elements is organized in functional, cell type-specific regulatory loops, which imitate the signaling structural hierarchy of the HPA axis. In melanocytes and fibroblasts CRH-induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway(s). Melanocytes respond with enhanced production of cortisol and corticosterone, which is dependent on POMC activity. Fibroblasts respond to CRH and ACTH with enhanced production of corticosterone, but not cortisol, which is produced constitutively. Organ-cultured human scalp hair follicles also show a fully functional HPA axis equivalent, including cortisol synthesis and secretion and negative feedback regulation by cortisol on CRH expression. Thus differential, CRH-driven responses of skin reproduce key features of the central HPA axis at the tissue/single cell levels.

Keywords: CRH, CRH-R1, POMC, cutaneous steroidogenesis, cutaneous P450scc, stress response

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