Histamine H4 receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge

Abstract

The present study observed effects of the histamine H(4) receptor on chronic allergic contact dermatitis induced by repeated challenge in mice. Acute contact dermatitis was induced by single epicutaneous challenge of 2,4,6-trinitro-1-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. 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 interleukin (IL)-4, -5, and -6 in lesions were decreased, whereas levels of interferon-gamma 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. 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.