Cutaneous expression of corticotropin‐releasing hormone (CRH), urocortin, and CRH receptors

Abstract

Studies in mammalian skin have shown expression of the genes for corticotropin-releasing hormone (CRH) and the related urocortin peptide, with subsequent production of the respective peptides. Recent molecular and biochemical analyses have further revealed the presence of CRH receptors (CRH-Rs). These CRH-Rs are functional, responding to CRH and urocortin peptides (exogenous or produced locally) through activation of receptor(s)-mediated pathways to modify skin cell phenotype. Thus, when taken together with the previous findings of cutaneous expression of POMC and its receptors, these observations extend the range of regulatory elements of the hypothalamic-pituitary-adrenal axis expressed in mammalian skin. Overall, the cutaneous CRH/POMC expression is highly reactive to common stressors such as immune cytokines, ultraviolet radiation, cutaneous pathology, or even the physiological changes associated with the hair cycle phase. Therefore, similar to its central analog, the local expression and action of CRH/POMC elements appear to be highly organized and entrained, representing general mechanism of cutaneous response to stressful stimuli. In such a CRH/POMC system, the CRH-Rs may be a central element.

Differential expression of HPA axis homolog in the skin

“…It is these mechanisms, as well as the precise coordination of their responses, that appear to be functionally served by local cutaneous neuroendocrine activities (Slominski, 2005;Slominski and Wortsman, 2000;Slominski et al, 2000d). Thus, cutaneous signals relayed to this local neuroendocrine system may trigger cascades of responses directed at maintaining local, and hence global, homeostasis (Slominski et al, 2004a;Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 2001;Slominski et al, 1999c;Zouboulis and Bohm, 2004).…”

“…In human skin, the production of CRH is associated with changes in the expression of the CRH gene, which is stimulated by UV radiation and forskolin and inhibited by dexamethasone (Slominski et al, 1996a;Slominski et al, 1998b;Zbytek et al, 2006). In mouse skin, there is hair-cycledependent production of CRH, even though corresponding changes in gene expression could not be detected (Roloff et al, 1998;Slominski et al, 1996c;Slominski et al, 2001;Slominski et al, 1999c). However, mouse skin expresses the gene for urocortin and produces the respective peptide (Slominski et al, 2000b).…”

“…CRH receptors-CRH-R1 and CRH-R2 are expressed in human Slominski et al, 1995;Slominski et al, 2000d;Slominski et al, 2001;Slominski et al, 1999c) and rodent (Pisarchik and Slominski, 2002;Roloff et al, 1998;Slominski et al, 1996c;Slominski et al, 2000d;Slominski et al, 1999c) skin, with species-specific compartmental localization. In the human skin, CRH-R1 is predominantly expressed in the epidermis with CRH-R1α being the major isoform present (Slominski et al, 2004a).…”

“…The cutaneous CRH-R1 is activated by CRH or urocortin and its intracellular signal transduction pathways are coupled to cAMP, IP3 or Ca (Fazal et al, 1998;Slominski et al, 2006b;Slominski et al, 1999c;Slominski et al, 2000e;Wiesner et al, 2003;Zbytek and Slominski, 2005). UV radiation and factors raising intracellular cAMP increase CRH-R1α expression and change the pattern of isoform expression Slominski et al, 2001). CRH-R1 participates in the regulation of skin cell proliferation, apoptosis, differentiation and immune activities (Carlson et al, 2001;Quevedo et al, 2001;Slominski, 2005;Slominski et al, 2000d;Slominski et al, 2006b;Zbytek et al, 2004;Zbytek and Slominski, 2005).…”

“…By analogy with the central response to systemic stress, we have proposed that the cutaneous response to local stressors is highly organized and mediated by a homolog of the central HPA axis, operating as local coordinator and executor (Slominski and Mihm, 1996;Slominski and Wortsman, 2000;Slominski et al, 2000d;Slominski et al, 2001;Slominski et al, 1999c). Mediators of this axis, i.e., CRH, urocortin and POMC peptides, would then regulate skin pigmentary, immune, epidermal, dermal and adnexal systems Ito et al, 2005;Kauser et al, 2006;Slominski, 2005;Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 1999c;Zbytek et al, 2004;Zouboulis et al, 2002).…”