Involvement of α-Melanocyte–Stimulating Hormone–Thromboxane A2 System on Itching in Atopic Dermatitis

Abstract

a-Melanocyteestimulating hormone (a-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. a-MSH elicits itch-related responses in mice. We, therefore, investigated whether a-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, a-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of a-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, melanocortin receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion of mice with dermatitis, mRNAs encoding MC1R, MC3R, and MC5R were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal a-MSH elicited itch-associated responses, which were inhibited by thromboxane (TX) A 2 receptor antagonist ONO-3708. In mouse keratinocytes, a-MSH increased the production of TXA 2 , which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca 2þ chelator EGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, a-MSHeinduced TXA 2 production was decreased. a-MSH increased intracellular Ca 2þ ion concentration in dorsal root ganglion neurons and keratinocytes. These results suggest that a-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA 2 production by keratinocytes.

Molecular and Cellular Mechanisms of Itch in Psoriasis

“…The expression levels of α-MSH and ACTH were previously shown to be higher in the lesional skin of psoriatic patients than in controls, but did not significantly differ from each other [62]. An intradermal injection of α-MSH induced itch-related scratching behavior in mice that was subsequently inhibited by a H 1 histamine receptor [65] or thromboxane A2 (TXA 2 ) antagonist [66]. In an atopic dermatitis murine model, the expression of α-MSH was mainly observed in keratinocytes, and scratching responses in these mice were attenuated by an antagonist of melanocortin 1 receptor (MC1R), which is one of the receptors of α-MSH [66].…”

“…An intradermal injection of α-MSH induced itch-related scratching behavior in mice that was subsequently inhibited by a H 1 histamine receptor [65] or thromboxane A2 (TXA 2 ) antagonist [66]. In an atopic dermatitis murine model, the expression of α-MSH was mainly observed in keratinocytes, and scratching responses in these mice were attenuated by an antagonist of melanocortin 1 receptor (MC1R), which is one of the receptors of α-MSH [66]. In addition, the production of TXA 2 , an α-MSH-induced itch modulator, was decreased by each small interference RNA (siRNA) for MC1R and melanocortin 5 receptor (MC5R) in keratinocytes [66].…”

“…In an atopic dermatitis murine model, the expression of α-MSH was mainly observed in keratinocytes, and scratching responses in these mice were attenuated by an antagonist of melanocortin 1 receptor (MC1R), which is one of the receptors of α-MSH [66]. In addition, the production of TXA 2 , an α-MSH-induced itch modulator, was decreased by each small interference RNA (siRNA) for MC1R and melanocortin 5 receptor (MC5R) in keratinocytes [66]. These findings indicate that α-MSH-MC1R/MC5R axis is also involved in the induction of psoriatic itch induced by psychological stress.…”

Antimelanogenic activities of piperlongumine derived from Piper longum on murine B16F10 melanoma cells in vitro and zebrafish embryos in vivo: its molecular mode of depigmenting action

“…Among them, eumelanin production is related to the involvement of three key enzymes as tyrosinase (TYR), tyrosine-relate protein-1 (TRP-1), and tyrosine-related protein-2 (TRP-2), referring to tyrosine conversion to construct melanin pigments [27]. Melanin synthesis or melanogenesis can be initiated by various paracrine cytokines such as α-melanocyte-stimulating hormone (α-MSH), which is used in this study as well as other studies [28,29]. Other cytokines as stem cell factor (SCF), endothelin-1, and nitric oxide have been known as triggers of melanogenesis under the exposure of UV-B irradiation [30][31][32].…”

The Molecular Mechanisms underlying the Therapeutic Effect of Berberine in Inflammatory Skin Diseases

“…Most of inflammatory skin diseases (e.g. atopic dermatitis and psoriasis) show epidermal hyperplasia that is seen as a thickening of the epidermis in human patients [61,62] and in mouse models [8,62]. In mouse model of atopic dermatitis [8] and psoriasis [62], berberine inhibits epidermal hyperplasia.…”