Histamine H_4 receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge

摘要

Background: The present study observed effects of the histamine H_4 receptor on chronic allergic contact dermatitis induced by repeated challenge in mice. Methods: Acute contact dermatitis was induced by single epicutaneous challenge of 2,4,6-trinitro-l-chlorobenzene (TNCB) to the ear. Chronic allergic contact dermatitis was developed by repeated epicutaneous challenge using TNCB on the dorsal back skin. H_4 receptor antagonist JNJ7777120 was administered to wild-type mice, while H_4 receptor agonist 4-methylhistamine was administered to histidine decarboxylase(HDC) (-/-) mice that synthesized no histamine.Results: HDC (-/-) mice did not differ phenotypically from HDC ( + / + ) mice, and H_4 receptor antagonist/agonist did not have clinical effects in terms of acute contact dermatitis reactions. H_4 receptor antagonist ameliorated skin eczematous lesions induced by repeated TNCB challenge in HDC (+ / +) mice. On the contrary, H_4 receptor agonist exacerbated skin lesions exclusively in HDC (-/-) mice. Application of H_4 receptor agonist induced migration of mast cells and eosinophils in skin lesions, and H_4 receptor antagonist suppressed these changes. H_4 receptor was immunohistochemically detected on mast cells in eczematous lesions. Levels of inter-leukin (IL)-4, -5, and -6 in lesions were decreased, whereas levels of interferon-y and IL-12 were increased by H_4 receptor antagonistic activity. Serum Immunoglobulin E levels rapidly increased with repeated challenge, but decreased with H_4 receptor antagonist.Conclusion: Because chronic allergic contact dermatitis is developed by H_4 receptor stimulation, H_4 receptor antagonists might represent new candidate drugs for treating chronic allergic contact dermatitis.