Effect of Histamine H4 receptor on allergic diseases

背景：本研究观察了组胺H4受体在反复激发所致小鼠慢性变态反应性接触性皮炎中的作用。方法：采用2，4，6-三硝基-1-氯苯(TNCB)耳部单次皮肤激发诱导小鼠急性接触性皮炎。慢性变态反应性接触性皮炎是通过在背部皮肤上反复使用TNCB进行皮下刺激而形成的。H4受体拮抗剂JNJ7777120用于野生型小鼠，H4受体激动剂4-甲基组胺用于不合成组胺的HDC(-/-)小鼠。结果：HDC(-/-)小鼠与HDC(+/+)小鼠没有明显的表型差异，H4受体拮抗剂/激动剂在急性接触性皮炎反应中没有临床疗效。H4受体拮抗剂可改善TnCB反复攻击HDC(+/+)小鼠所致的皮肤湿疹。相反，H4受体激动剂仅在HDC(-/-)小鼠身上加重皮肤损害。应用H4受体激动剂可诱导皮损中肥大细胞和嗜酸性粒细胞的迁移，而H4受体拮抗剂可抑制这些变化。应用免疫组织化学方法检测湿疹皮损中肥大细胞H4受体的表达。H4受体拮抗作用使皮损中IL-4、-5和-6水平降低，而干扰素-γ和IL-12水平升高。结论：慢性变态反应性接触性皮炎是由H4受体刺激引起的，H4受体拮抗剂有可能成为治疗慢性变应性接触性皮炎的新候选药物。

Background : The present study observed effects of the histamine H4 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-1-chlorobenzene (TNCB) to the ear. Chronic allergic contact dermatitis was developed by repeated epicutaneous challenge using TNCB on the dorsal back skin. H4 receptor antagonist JNJ7777120 was administered to wild-type mice, while H4 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 H4 receptor antagonist/agonist did not have clinical effects in terms of acute contact dermatitis reactions. H4 receptor antagonist ameliorated skin eczematous lesions induced by repeated TNCB challenge in HDC (+/+) mice. On the contrary, H4 receptor agonist exacerbated skin lesions exclusively in HDC (-/-) mice. Application of H4 receptor agonist induced migration of mast cells and eosinophils in skin lesions and H4 receptor antagonist suppressed these changes. H4 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-γ and IL-12 were increased by H4 receptor antagonistic activity. Serum Immunoglogulin E levels rapidly increased with repeated challenge, but decreased with H4 receptor antagonist.Conclusion : Since chronic allergic contact dermatitis is developed by H4 receptor stimulation, H4 receptor antagonists might represent new candidate drugs for treating chronic allergic contact dermatitis.