Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Abstract

Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 ␤-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11␤-hydroxysteroid dehydrogenase 2 (11␤HSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1␤, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1␤ production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.Acute wound healing is a complex biological process mediated by a network of signaling pathways that coordinate multiple cellular processes, including cellular migration and proliferation, ultimately leading to barrier restoration (1). Wound healing is a tightly spatiotemporally regulated process, and changes in any component of this process can be detrimental, leading to further tissue damage or impairment of healing (2, 3).For example, timing of inflammatory response is essential; proinflammatory signals are important in the early stage of healing, but they can be detrimental if they persist (4, 5), underscoring a need for tight control of both stimulators and inhibitors during the wound healing process.Upon injury, keratinocytes are the first cells that respond (6, 7) by releasing pre-stored interleukin-1 (IL-1) (8). IL-1 has an autocrine and a paracrine function; that is, to activate keratinocytes and to alert the surrounding cells and tissues. The release of IL-1 by keratinocytes, with subsequent release of additional signaling molecules (9, 10), demarcates the proinflammatory phase of wound healing. In response to these signals, activated keratinocytes start migrating and proliferating (7,8,11). Successful repair after tissue injury requires resolution of inflammatory response, transitioning keratinocyte (HEK) from activated to differentiating phenotype. However, very little is known about endogenous epidermal signals that control keratinocyte activation cycle and inflammatory response.Epidermal keratinocytes have important immunol...

Low environmental humidity induces synthesis and release of cortisol in an epidermal organotypic culture system

“…IL-1b also increases cortisol generation in cultured human keratinocytes (7). Adrenocorticotropic hormone (ACTH) and progesterone also increase cortisol generation, and their effects are blocked by CYP11B1 inhibitor (7). Thus, all the components of the hypothalamo-pituitary-adrenal (HPA) axis appear to be present in epidermal keratinocytes.…”

“…Moreover, injured epidermal keratinocytes secrete IL-1b, which induces increased CYP11B1 expression and cortisol secretion. IL-1b also increases cortisol generation in cultured human keratinocytes (7). Adrenocorticotropic hormone (ACTH) and progesterone also increase cortisol generation, and their effects are blocked by CYP11B1 inhibitor (7).…”

Local cortisol activation is involved in EGF-induced immunosuppression

“…1G). We suspect that this difference is because supernatant cortisol concentrations in keratinocytes reflect cortisol produced by both the de novo pathway through CYP11A1 and CYP11B1 18 and the activating pathway through 11b-HSD1. In addition, most of the cortisol produced in cells binds to glucocorticoid receptors and only minimal amounts of cortisol are released into the supernatant.…”

Extra-Adrenal Glucocorticoid Synthesis in Mucosal Tissues and Its Implication in Mucosal Immune Homeostasis and Tumor Development

“…Human skin has been demonstrated to respond to ACTH, to express various steroidogenic enzymes, and to be capable of synthesizing cortisol [8,18]. Local steroidogenesis was demonstrated in human keratinocytes [19], sebaceous cells [18], fibroblasts [14], and melanocytes [13]. Hair follicles, also known as pilosebaceus units, appear to function as fully autonomous peripheral equivalents of the HPA axis.…”