Inducible histamine protects mice from P.acnes-primed and LPS-induced hepatitis through H2-receptor stimulation

诱导型组胺和组胺H2受体被认为参与先天性免疫应答。我们研究了诱导型组胺在痤疮丙酸杆菌致敏和脂多糖诱导的肝炎中对肝损伤和致死性的保护作用，使用紫藤苷脱羧酶敲除和H2受体敲除小鼠。痤疮丙酸杆菌引发后的脂多糖攻击增加了野生型小鼠肝脏中组氨酸脱羧酶的活性，与组胺周转率的显著升高相关。在CD 68阳性枯否细胞/巨噬细胞中观察到组氨酸脱羧酶样免疫反应性。用法莫替丁或雷尼替丁而不是d-氯苯那敏治疗野生型小鼠，增加了肝损伤，显著抑制了存活率。相同剂量的痤疮丙酸杆菌和脂多糖可使组氨酸脱羧酶基因敲除小鼠和H2受体基因敲除小鼠发生重度肝炎和高致死率，前者可通过皮下注射组胺进行挽救。免疫组化研究支持组胺对肝细胞凋亡的保护作用。组胺抑制肝脏中IL-18和肿瘤坏死因子-α的表达，导致血浆细胞因子水平降低，包括IL-18、TNF-α、IL-12、IFN-γ和IL-6。这些结果作为一个整体表明，内源性产生的组胺Kupffer细胞/巨噬细胞发挥了非常重要的作用，防止过度的先天性免疫反应，内毒素诱导的暴发性肝炎，通过刺激H2受体。

Inducible histamine and histamine H2-receptors have been suggested to be involved in innate immune response. We examined a functional role of inducible histamine in the protection against hepatic injury and lethality in Propionibacterium acnes-primed and lipopolysaccharide-induced hepatitis, using wistidine decarboxylase knockout and H2-receptor knockout mice. Lipopolysaccharide challenge after Propionibacterium acnes-priming increased histidine decar boxylase activity in the liver of wild-type mice, associated with a marked elevation of histamine turnover. Histidine decarboxylase-like immunoreactivity was observed in CD68-positive Kupffer cells/macrophages. Treatment of wild-type mice with famotidine or ranitidine but not d-chlorpheniramine augmented hepatic injury and inhibited the survival rate significantly. The same dose of Propionibacterium acnes and lipopolysaccharide induced severe hepatitis and high lethality in histidine decarboxylase knockout and H2-receptor knockout mice, the former were rescued by the subcutaneous injection of histamine. Immunohistochemical study supported the protective role of histamine against the apoptosis of hepatocytes. Histamine suppressed the expression of IL-18 and tumor necrosis factor-α in the liver, leading to the reduced plasma levels of cytokines including IL-18,TNF-α,IL-12,IFN-γ and IL-6. These findings as a whole indicated that endogenously produced histamine in Kupffer cells/macrophages plays a very important role in preventing excessive innate immune response in endotoxin-induced fulminant hepatitis through the stimulation of H2-receptors.