CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH

Abstract

The response to systemic stress is organized along the hypothalamic-pituitary-adrenal axis (HPA), whereas the response to a peripheral stress (solar radiation) is mediated by epidermal melanocytes (cells of neural crest origin) responsible for the pigmentary reaction. Melanocytes express proopiomelanocortin (POMC), corticotropin-releasing hormone (CRH), and CRH receptor-1 (CRH-R1) and can produce corticosterone. In the present study, incubation of normal epidermal melanocytes with CRH was found to trigger a functional cascade structured hierarchically and arranged along the same algorithm as in the HPA axis: CRH activation of CRH-R1 stimulated cAMP accumulation and increased POMC gene expression and production of ACTH. CRH and ACTH also enhanced production of cortisol and corticosterone, and cortisol production was also stimulated by progesterone. The chemical identity of the cortisol was confirmed by liquid chromatography-mass spectrometry (LC/MS2) with [corrected] mass spectrometry-mass spectrometry analyses. POMC gene silencing abolished the stimulatory effect of CRH on corticosteroid synthesis, indicating that this is indirect and mediated via production of ACTH. Thus the melanocyte response to CRH is highly organized along the same functional hierarchy as the HPA axis. This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels.

Differential expression of HPA axis homolog in the skin

“…The key tenants of the above hypothesis are now firmly supported by experimental evidence (Ito et al, 2005;Slominski et al, 2005e;Slominski et al, 2005f). For example, incubation of normal epidermal melanocytes and dermal fibroblasts with CRH triggers a functional cascade, which is structured hierarchically along the same algorithm as in the HPA axis: CRH activates CRH-R1; this stimulates cAMP accumulation which increases POMC gene expression and production of ACTH (Slominski et al, 2005f). While this sequence was not detected in cultured, isolated keratinocytes, melanocytes respond to CRH and ACTH with enhanced production of cortisol and corticosterone, an effect abolished by POMC gene silencing or by the potent CRH-R1 antagonist, antalarmine (Slominski et al, 2005f).…”

“…Signals generated by the integrated actions of these peptides would counteract the local effects of the stressor agent and also attenuate the attendant cutaneous responses (Slominski, 2005;Slominski and Wortsman, 2000;Slominski et al, 2000d). The key tenants of the above hypothesis are now firmly supported by experimental evidence (Ito et al, 2005;Slominski et al, 2005e;Slominski et al, 2005f). For example, incubation of normal epidermal melanocytes and dermal fibroblasts with CRH triggers a functional cascade, which is structured hierarchically along the same algorithm as in the HPA axis: CRH activates CRH-R1; this stimulates cAMP accumulation which increases POMC gene expression and production of ACTH (Slominski et al, 2005f).…”

“…Also, corticosterone and cortisol production has been shown by cultured normal human melanocytes and fibroblasts (Slominski et al, 2005e;Slominski et al, 2005f;Slominski et al, 2006c). Therefore, human skin is an extraadrenal site of glucocortidoid synthesis and expresses a steroidogenic pathway suitable for operation in intra-, auto or paracrine modes of action.…”

Involvement of Nurr-1/Nur77 in corticotropin-releasing factor/urocortin1-induced tyrosinase-related protein 1 gene transcription in human melanoma HMV-II cells

“…Indeed, mammalian skin expresses CRF, its related peptide, urocortin (Ucn), their corresponding receptors, POMC, which is further processed to -endorphin, ACTH, and -MSH, and glucocorticoids (Slominski et al, 2000b;Slominski et al, 2001;Slominski et al, 2005a;Slominski et al, 2006b). CRF also stimulates POMC gene expression and its subsequent production in human melanocytes (Slominski et al, 2005b). Both CRF and POMC are produced in ultraviolet B-irradiated human melanocytes.…”

“…Additionally, CRF regulates cell viability, proliferation, and migration in skin cells (Slominski et al, 2006a;Yang et al, 2007). CRF also stimulates glucocorticoid production through ACTH production in melanocytes and human scalp hair follicles (Slominski et al, 2005b;Ito et al, 2005), while CRF and Ucn1 stimulate expression of tyrosinase-related enzymes in human hair follicle melanocytes (Kauser et al, 2006). Nur77, also known as nerve growth factor-inducible factor-B (NGFI-B), and Nurr-1 are involved in CRF-induced POMC expression in corticotrophs (Philips et al, 1997: Murphy andConneely, 1997;Kovalovsky et al, 2002).…”