Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders

Abstract

Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2 and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6 and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

Glucocorticoid-dependent transcription in skin requires epidermal expression of the glucocorticoid receptor and is modulated by the mineralocorticoid receptor

“…GC synthesis and release are under the control of the hypothalamic–pituitary–adrenal neuroendocrine axis, which acts as a major regulator of skin integrity and function. In addition to the adrenal source of GCs, the skin can produce steroidogenic enzymes and extra-adrenal GCs, allowing for an immediate tissue-specific response 21 . Local GC synthesis occurs in both epidermis and dermis, and plays a major role in cutaneous homeostasis and pathological conditions 22 – 27 .…”

Pathogenesis of psoriasis in the “omic” era. Part III. Metabolic disorders, metabolomics, nutrigenomics in psoriasis in psoriasis

“…The data on lipocalin-2 and retinol binding protein (RBP)-4 are conflicting and further studies are required [12]. In addition, the adipose tissue has the capability of producing proopiomelanocortin (POMC) derived peptides with anti-inflammatory activities and is involved in glucosteroidogenesis [38,39].…”

Current and emerging treatments targeting the neuroendocrine system for disorders of the skin and its appendages

“…It has been shown that the skin is a corticosteroidogenic organ with a capability for steroid synthesis starting from cholesterol. [5][6][7][8][9][10] Human hair follicles are also able to produce cortisol. [11] Synthetic corticosteroids, in use since 1950s, are the most prescribed drugs for treatment of skin diseases such as atopic dermatitis (AD), psoriasis, vitiligo, lichen planus and other inflammatory skin diseases and are not the focus of this review, for more details, please read specialized reviews.…”