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Effect of Histamine H4 receptor on allergic diseases

组胺H4受体对过敏性疾病的影响

基本信息

批准号：
19591194
负责人：
SEIKE Masahiro
金额：
$ 3.16万
依托单位：
Sagami Women's Junior College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19591194/
关键词：
ヒスタミン知覚神経皮膚炎 H4受容体アレルギー性皮膚炎肥満細胞好酸球慢性アレルギー性皮膚炎慢性アレルギー性接触皮膚炎 Th1 Th2 サイトカイン皮膚アレルギー反応接触皮膚炎ヒスタミン第4受容体 IgE

项目摘要

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.

背景：本研究观察组胺 H4 受体对小鼠反复刺激引起的慢性过敏性接触性皮炎的影响。方法：通过将 2,4,6-三硝基-1-氯苯（TNCB）单次表皮刺激到耳朵诱发急性接触性皮炎。慢性过敏性接触性皮炎是通过在背背皮肤上使用 TNCB 反复进行表皮刺激而产生的。将 H4 受体拮抗剂 JNJ7777120 给予野生型小鼠，同时将 H4 受体激动剂 4-甲基组胺给予不合成组胺的组氨酸脱羧酶 (HDC) (-/-) 小鼠。结果：HDC (-/-) 小鼠与 HDC (+/+) 小鼠和 H4 受体在表型上没有差异拮抗剂/激动剂对急性接触性皮炎反应没有临床效果。 H4 受体拮抗剂可改善 HDC (+/+) 小鼠反复 TNCB 激发引起的皮肤湿疹病变。相反，H4 受体激动剂仅在 HDC (-/-) 小鼠中加剧皮肤损伤。应用H4受体激动剂诱导皮损中肥大细胞和嗜酸性粒细胞的迁移，而应用H4受体拮抗剂则抑制这些变化。通过免疫组织化学方法在湿疹皮损的肥大细胞上检测到 H4 受体。 H4 受体拮抗活性使病灶中白细胞介素 (IL)-4、-5 和 -6 的水平降低，而干扰素-γ 和 IL-12 的水平升高。血清免疫球蛋白E水平随重复攻击而迅速升高，但随H4受体拮抗剂而降低。结论：由于慢性过敏性接触性皮炎是由H4受体刺激引起的，因此H4受体拮抗剂可能是治疗慢性过敏性接触性皮炎的新候选药物。