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

诱导组胺通过 H2 受体刺激保护小鼠免受痤疮丙酸杆菌引发和 LPS 诱导的肝炎

• 批准号: 15590467
• 负责人: TAKAHASHI Hideo
• 金额: $ 2.3万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590467/
• 关键词: histamine; H2-receptors; hepatic injury; knockout mice; IL-18; Lipopolysaccharide; Propionibacterium acnes; Kupffer cells; macrophages; 肝炎治療; HDC; 細胞間シグナル伝達; アポトーシス

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.

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。

项目成果

Beta 2-adrenergic receptor agonist induces IL-18 production without IL-l2 production.

β2-肾上腺素能受体激动剂诱导IL-18产生而不产生IL-12。

• 发表时间: 2004
• 期刊: Journal of Neuroimmunology 151(1-2)
• 作者: Takahashi HK;Takahashi HK;Takahashi HK;Takahashi HK;Takahashi HK;Yokoyama M;Takahashi HK;Takahashi HK;Kubo S;Tamura R;Takahashi HK;Kubo S;Takahashi HK;Takahashi HK;Takahashi HK
• 通讯作者: Takahashi HK

Takahashi HK: "Unique regulation profile of prostaglandin e1 on adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells"J Pharmacol Exp Ther.. 307. 1188-1195 (2003)

Takahashi HK：“前列腺素 e1 对人外周血单核细胞粘附分子表达和细胞因子产生的独特调节特征”J Pharmacol Exp Ther.. 307. 1188-1195 (2003)

The regulation of ICAM-1 and LFA-1 interaction by autacoids and statins : a novel strategy for controlling inflammation and immune responses.

自体激素和他汀类药物对 ICAM-1 和 LFA-1 相互作用的调节：控制炎症和免疫反应的新策略。

• 发表时间: 2003
• 期刊: Journal of Pharmacological Sciences 92(1)
• 作者: Takahashi HK;Takahashi HK;Yokoyama M;Takahashi HK;Takahashi HK;Takahashi HK;Mori S;Kubo S;Tamura R;Yokoyama et al.;Takahashi et al.;Takahashi HK;Takahashi HK;Jikuhara A;Takahashi HK;Nishibori M
• 通讯作者: Nishibori M

Effect of beta2-adrenergic receptor agonists on intercellular adhesion molecule (ICAM)-1,B7,and CD40 expression in mixed lymphocyte reaction.

β2-肾上腺素能受体激动剂对混合淋巴细胞反应中细胞间粘附分子 (ICAM)-1、B7 和 CD40 表达的影响。

• 发表时间: 2004
• 期刊: Transplantation 77(2)
• 作者: Takahashi HK;Takahashi HK;Yokoyama M;Takahashi HK;Takahashi HK;Takahashi HK;Mori S;Kubo S;Tamura R
• 通讯作者: Tamura R

Unique regulation profile of prostaglandin e1 on adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells.

前列腺素 e1 对人外周血单核细胞粘附分子表达和细胞因子产生的独特调节特征。

• 发表时间: 2003
• 期刊: J.Pharmacology and Experimental Therapeutics 307(3)
• 作者: Takahashi HK;Takahashi HK;Yokoyama M;Takahashi HK;Takahashi HK;Takahashi HK;Mori S;Kubo S;Tamura R;Yokoyama et al.;Takahashi et al.;Takahashi HK;Takahashi HK
• 通讯作者: Takahashi HK