Keratinocytes synthesize and activate cortisol

Abstract

The bioavailability of circulating and/or endogenous hydrocortisone (cortisol) in epidermal cells is a key determinant in inflammatory disease and chronic wounds. It is not known, however, whether epidermal cells can regulate tissue cortisol and whether they are capable of producing endogenous glucocorticoids. In the present study, we show by microarray analysis that epidermal cells express mRNAs to all the major enzymes involved in the metabolic chain from cholesterol to cortisol, including cytocrome P450 chain, 11β-hydroxysteroid dehydrogenases (HSD11Bs), adrenocorticotropic hormone (ACTH) receptor (MC2R), and glucocorticoid receptor. The two enzymes mediating activation/deactivation of cortisone to cortisol, namely HSD11B1 and HSD11B2, were expressed at the protein level in cultured keratinocytes as well as human skin samples, as shown by Western blotting and immunohistochemistry, respectively. In functional assays, we show that keratinocytes are not only able to activate cortisone to cortisol in a HSD11B-dependent manner but also silencing of either HSD11B1 or HSD11B2 specifically modulates the bioavailability of the inactive glucocorticoid and the active steroid, respectively. A further key observation was that keratinocytes responded to stimulation with ACTH by a significant increase in the de novo synthesis of cortisol. Taken together, we provide evidence for a novel non-adrenal steroideal system in human keratinocytes.

Increased glucocorticoid activation during mouse skin wound healing

“…Although our studies were conducted in mice, the ability of human skin to synthesize cortisol de novo also remains debatable, with studies reporting both negative (Slominski et al 2002) and positive findings (Cirillo & Prime 2011, Hannen et al 2011, Vukelic et al 2011. Moreover, the quantities of cortisol generated de novo in these studies appear to be considerably lower than those reported to be generated by 11b-HSD1 in human skin (Tiganescu et al 2011(Tiganescu et al , 2013.…”

“…Expression of steroidogenic enzymes in this pathway, including cytochromes CYP11A1, CYP17A1, and CYP21A2 has been detected in human skin (Slominski et al 1996), with cortisol synthesis detected in hair follicles (Ito et al 2005), keratinocytes (Cirillo & Prime 2011, Hannen et al 2011, Vukelic et al 2011, melanocytes (Slominski et al 2005a), and fibroblasts (Slominski et al 2005b(Slominski et al , 2006. Corticosterone synthesis has also been detected in rodent skin (Slominski et al 2000a).…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…11␤-HSD1 is widely expressed in human and mouse epidermis and dermis (276,699), but is highest in keratinocytes in the suprabasal area of the epidermis and dermal fibroblasts where it is a reductase (121). Keratinocyte 11␤-HSD1 increases with differentiation (699), parallelling the enzyme's pattern during differentiation of preadipocytes (510).…”

Synthesis, activation and deactivation of glucocorticoids. The biological role of cortisol in metabolic disorders

“…Наряду с тканью надпочечников, синтезирующей глюкокортикоиды, все больше данных стало появ-ляться о местах вненадпочечниковой продукции кор-тизола, к ним относятся мозг, легкие, сердце, тимус, клети иммунной системы и кожа [21,22].…”

“…Люди с ожирением имеют высокий риск развития венозных язв, различных кожных забо-леваний (например, кандидоза, эритразмы) или более серьезных кожных инфекций (например, целлюлита, некротизирующего фасцита), гнойных осложнений после хирургических вмешательств. Однако роль ГКС в регуляции репарации ран в настоящее время доста-точно плохо изучена.Наряду с тканью надпочечников, синтезирующей глюкокортикоиды, все больше данных стало появ-ляться о местах вненадпочечниковой продукции кор-тизола, к ним относятся мозг, легкие, сердце, тимус, клети иммунной системы и кожа [21,22].Несмотря на основную функцию кожи служить барьером для защиты внутренней среды организма от агрессивных воздействий, последние исследова-ния в дерматологии были посвящены изучению спо-собности клеток эпидермиса секретировать гормоны. Способность взаимодействовать с центральной нерв-ной системой посредством локальной продукции в системный кровоток гормонов, нейропептидов, ней-ротрансмиттеров и других регуляторных факторов по-зволяет рассматривать кожу как нейроэндокринный орган [23].…”