Steroidogenesis in the skin: implications for local immune functions

Abstract

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.

Keywords: 11-hydroxysteroiddehydrogenase type 1; 11-hydroxysteroiddehydrogenase type 2; 11β-hydroxylase type 1; 11β-hydroxylase type 2; 17β-HSD; 17β-hydroxysteroid dehydrogenase; 21-hydroxylase; 3α-HSD; 3α-hydroxysteroid dehydrogenase; 3β-HSD; 3β-hydroxysteroid dehydrogenase; 5α-reductase; 5αR; ACTH; Androgen; CD; CRH; CYP11A1; CYP11A1 or P450scc; CYP11B1; CYP11B2; CYP17A1 or P450c17; CYP21; DAX-1; DHEA; DHT; DOC; DPCs; E1; E2; ECM; ERE; ERR; Estrogen; GM-CSF; GR; Glucocorticoids; HF; HPA; HS; HSD11B1 or 11-HSD 1; HSD11B2 or 11-HSD 2; INF; IRSKS; LE; MHC; MR; NFkB; NHEKs; ORSKs; POMC; SF-1; SP; SSc; Skin endocrine system; Skin immune system; StAR; T; T helper; TGFβ; Th; UVR; adrenocorticotropic hormone; cAMP-dependent protein kinase A; cAMP/PKA; cluster of differentiation; corticotrophin releasing hormone; cytochrome P450 17α-hydroxylase/17,20-lyase; cytochrome P450 side-chain cleavage enzyme; dehydroepiandrosterone; deoxycorticosterone; dermal papilla cells; dihydrotestosterone; dosage-sensitive sex-reversal-adrenal hypoplasia congenital critical region on the x-chromosome, gene 1; estradiol; estrogen response element; estrogen-related receptor; estrone; extracellular matrix; glucocorticoid receptor; granulocyte-macrophage colony-stimulating factor; hair follicle; hidradenitis suppurativa/acne inversa; hypothalamus–pituitary–adrenal gland; inner root sheath keratinocytes; interferon; lupus erythematosus; major histocompatibility complex; mineralocorticoid receptor; normal human epidermal keratinocytes; nuclear factor kappa-light-chain-enhancer of activated B cells; outer root sheath keratinocytes; proopiomelanocortin; steroidogenic acute regulatory protein; steroidogenic factor 1; substance P; systemic sclerosis; testosterone; transforming growth factor β; ultraviolet radiation.