Genetic variation of the cutaneous HPA axis: An analysis of UVB-induced differential responses

Abstract

Mammalian skin incorporates a local equivalent of the hypothalamic-pituitary-adrenal (HPA) axis that is critical in coordinating homeostatic responses against external noxious stimuli. Ultraviolet radiation B (UVB) is a skin-specific stressor that can activate this cutaneous HPA axis. Since C57BL/6 (B6) and DBA/2J (D2) strains of mice have different predispositions to sensorineural pathway activation, we quantified expression of HPA axis components at the gene and protein levels in skin incubated ex vivo after UVB or sham irradiation. Urocortin mRNA was up-regulated after all doses of UVB with a maximum level at 50 mJ/cm2 after 12 h for D2 and at 200 mJ/cm2 after 24 h for B6. Proopiomelanocortin mRNA was enhanced after 6 h with the peak after 12 h and at 200 mJ/cm2 for both genotypes of mice. ACTH levels in tissue and media increased after 24 h in B6 but not in D2. UVB stimulated β-endorphin expression was higher in D2 than B6. Melanocortin receptor 2 mRNA was stimulated by UVB in a dose-dependent manner, with a peak at 200 mJ/cm2 after 12 h for both strains. The expression of Cyp11a1 mRNA — a key mitochondrial P450 enzyme in steroidogenesis, was stimulated at all doses of UVB irradiation, with the most pronounced effect after 12–24 h. UVB radiation caused, independently of genotype, a dose-dependent increases in corticosterone production in the skin, mainly after 24 h of histoculture. Thus, basal and UVB stimulated expression of the cutaneous HPA axis differs as a function of genotype: D2 responds to UVB earlier and with higher amplitude than B6, while B6 shows prolonged (up to 48 h) stress response to a noxious stimulus such as UVB.

Protective Effect of Indole-3-Pyruvate against Ultraviolet B-Induced Damage to Cultured HaCaT Keratinocytes and the Skin of Hairless Mice

“…In response to UVB-irradiation, epidermal and dermal cells produce stress neurotransmitters, neuropeptides and hormones [5], [6]. Increased expression of HPA axis gene is observed in UVB-irradiated skin or co-culture model using keratinocyte and melanocyte [6], [7].…”

Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation

“…We have discovered novel secosteroidogenic pathway(s) operating in vivo [41, 42, 83, 84], for which the major products also protect keratinocytes and melanocytes against UVB-induced oxidative stress and DNA damage, as shown in this study. Of note is the expression of the enzyme that initiates and regulates these novel secosteroidogenic pathways, CYP11A1, which is also be upregulated by UVB [85, 86]. Therefore, we propose that the activities of the classical (producing 1,25(OH) 2 D3) and novel (producing 20(OH)D3 and 20,23(OH) 2 D3) secosteroidogenic enzyme systems regulate the protection of the human epidermis against UVB exposure by attenuating DNA- and metabolic-damage via several mechanisms.…”

The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

“…To restore skin homeostasis in response to UVB induced harm, several signalling cascades such as the cutaneous neuroendocrine hypothalamic-pituitary-adrenal axis and pathways resulting in the stabilisation of p53 are activated [27, 37–40]. The tumor suppressor p53 has an important cellular gatekeeper function maintaining genomic stability in response to cellular stress, such as UVB induced DNA-damage, by inducing DNA-repair or apoptosis [38].…”