GROWTH FACTORS, CYTOKINES, AND CELL CYCLE MOLECULES
Histamine Released from Epidermal Keratinocytes Plays a Role in a-MelanocyteeStimulating Hormone-Induced Itching in Mice
Kyoko Shimizu,* Tsugunobu Andoh,y Yoko Yoshihisa,* and Tadamichi Shimizu*
From the Departments of Dermatology* and Applied Pharmacology,y Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Sunburn, wound repair, and chronic renal failure with hemodialysis are usually accompanied by both pigmentation and itching. Proopiomelanocortin-derived a-melanocyteestimulating hormone (a-MSH) is produced in response to external stimuli, such as UV irradiation, and is involved in cutaneous pigmen- tation. However, it is unclear whether a-MSH is also involved in the itching. We therefore investigated whether a-MSH elicited itch-related responses in mice. We found that an intradermal injection of a-MSH induced hind-paw scratching, an itch-related response, in mice. The a-MSHeinduced scratching was inhibited by the m-opioid receptor antagonist naltrexone and the H1 histamine receptor antagonist terfenadine. In mast cell-deficient mice, a-MSH also elicited scratching, which was inhibited by terfe- nadine. The immunoreactivity for L-histidine decarboxylase, a key enzyme required for the production of histamine, histamine, and the melanocortin 1 and 5 receptors were shown in not only mast cells but also keratinocytes in murine skin. In addition to the expression of L-histidine decarboxylase and melanocortin 1 and 5 receptors, the mouse keratinocyte cell lines (Pam212) also showed immunoreactivity for L-histidine decarboxylase, histamine, and melanocortin 1 and 5 receptors. The application of a-MSH induced the release of histamine from Pam212 cells. These findings indicate that a-MSH may play an important role in the itching associated with pigmented cutaneous lesions and that the histamine released from keratinocytes is involved in this a-MSHeinduced itching. (Am J Pathol 2015, 185: 3003e3010; http://dx.doi.org/10.1016/j.ajpath.2015.07.015)
