Corticotropin Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress

Abstract

The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides alpha-melanocyte stimulating hormone (alpha-MSH), beta-endorphin, and ACTH and also a source of these peptides. Skin expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase), ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA, POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants. The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and mu-opiate, although most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant immune reactions.

α‐melanocyte–stimulating hormone suppresses bleomycin‐induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: Melanocortin peptides as a novel treatment strategy for scleroderma?

“…With regard to the detected expression of POMC in the skin of SSc patients, it should be noted that normal human skin and various cutaneous cell types in vitro express POMC autonomously and have the full capacity to make melanocortin peptides (10,11,43,44). POMC expression per se does not impair the response of skin cells to ␣-MSH (9-13).…”

“…Alpha-melanocyte-stimulating hormone is derived from pro-opiomelanocortin (POMC), both of which are produced by the skin itself (11). In addition to its pigmentary action (12), ␣-MSH has many other effects, such as immunomodulation and regulation of exocrine activity and apoptosis (13)(14)(15).…”

Differential expression of HPA axis homolog in the skin

“…The strategic location of the skin as a barrier between the environment and the internal milieu determines its critical function in the preservation of body homeostasis (Slominski, 2005;Slominski and Wortsman, 2000;Slominski et al, 2000d). The skin is continuously exposed to many hostile environmental factors (chemical and biological) and to acute transfers of solar, thermal or mechanical energy (Slominski and Pawelek, 1998;Slominski and Wortsman, 2000;Slominski et al, 2000d).…”

“…The skin is continuously exposed to many hostile environmental factors (chemical and biological) and to acute transfers of solar, thermal or mechanical energy (Slominski and Pawelek, 1998;Slominski and Wortsman, 2000;Slominski et al, 2000d). In part as a mechanism of defense, skin cells produce hormones, neurotransmitters and neuropeptides and express cognate functional receptors Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 2000d).…”

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

“…Melanocytes are a type of sensory and regulatory cell with neuroendocrine activity (Tsatmali et al, 2002), producing stress-related neurotransmitters and neuropeptides in response to various endogenous and exogenous factors derived from neighboring keratinocytes (Slominski, 2009;Slominski and Wortsman, 2000). Cutaneous melanin pigmentation occurs in response to external and internal stresses (Slominski et al, 2000a;Slominski et al, 2004b;Ito et al, 2005).…”