Innate immune response to gut-derived bacterial toxins in gastrointestinal andhepatic disorders

胃肠道和肝脏疾病中对肠源性细菌毒素的先天免疫反应

• 批准号: 12470129
• 负责人: SATO Nobuhiro
• 金额: $ 7.36万
• 依托单位: Juntendo University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470129/
• 关键词: bacterial toxins; innate immunity; alcoholic liver disease; inflammatory bowel diseases; macrophages; Toll-like receptor (TLR); glycine; Kupffer細胞; CD14; Toll-like receptor; TNF-α; 炎症性腸疾患; Toll-like receotor(Tlr); LPS binding protein; Toll-l

Increasing lines of evidence have suggested a possible involvement of gut-derived bacterial toxins in various kinds of gastrointestinal and hepatic disorders including inflammatory bowel diseases (IBDs) and alcoholic liver disease (ALD). In the present study, we investigated the role of innate immune system that recognizes bacterial toxins [i.e., endotoxin (lipopolysaccharide, LPS) from Gram-negative bacteria] in ALD and IBDs.Regarding the pathogenesis of ALD, we investigated the expression pattern of Toll-like receptor (TLR)-4 and its downstream signaling molecules in the liver following acute ethanol treatment in mice. TLR-4 mRNA was detected constitutively in the normal liver tissue; however, it was decreased almost 90% within 6 hr after a single intragastric injection of ethanol (5 g/kg BW), followed by a gradual increase to the basal levels in 24 hr. In contrast, interleukin- 1 receptor associated kinase (IRAK) protein levels and its activity in Kupffer cells were increased 21 hr … More after acute ethanol injection. These findings most likely explain the mechanism of tolerance and sensitization of Kupffer cell to LPS in ethanol intoxication. Further, we evaluated the effect of thalidomide in an experimental model of alcoholic hepatitis in the rat. Thalidomide prevented activation of Kupffer cells due to gut-derived endotoxin , thereby protecting from alcohol-induced liver injury. This approach appears to be useful in patients of severe alcoholic hepatitis. In addition, we developed a new immuno-nutritional approach to IBDs using glycine, a non-essential amino acid. Glycine has been shown to prevent activation of macrophages and neutrophils due to bacterial toxins. In the present study, therefore, we evaluated whether dietary glycine prevents chemical-induced experimental colitis in the rats. Glycine prevented both TNBS- and DSS-induced colitis, which represent human Crohn's disease and ulcerative colitis, respectively, by decreasing induction of inflammatory cytokines and chemokines in the colonic tissue. It is postulated that glycine is useful for therapeutics of IBDs based on the mechanism that involves modulation of the innate immune system in the gut Less

越来越多的证据表明，肠道来源的细菌毒素可能参与各种胃肠道和肝脏疾病，包括炎症性肠病（IBD）和酒精性肝病（ALD）。在本研究中，我们研究了识别细菌毒素的先天免疫系统的作用[即，关于ALD的发病机制，我们研究了急性乙醇处理后小鼠肝脏中Toll样受体（TLR）-4及其下游信号分子的表达模式。TLR-4 mRNA在正常肝组织中呈组成型表达，但在单次灌胃乙醇（5g/kg BW）后6 h内下降近90%，24 h后逐渐升高至基础水平，而库普弗细胞中白细胞介素-1受体相关激酶（IRAK）蛋白水平及其活性在21 h后升高 ...更多信息 急性乙醇注射后。这些发现很可能解释了乙醇中毒时枯否细胞对LPS的耐受和增敏机制。此外，我们评估了沙利度胺在大鼠酒精性肝炎实验模型中的作用。沙利度胺可防止因肠源性内毒素引起的枯否细胞活化，从而防止酒精诱导的肝损伤。这种方法似乎对重度酒精性肝炎患者有用。此外，我们开发了一种新的免疫营养方法，使用甘氨酸，一种非必需氨基酸。甘氨酸已被证明可以防止由于细菌毒素引起的巨噬细胞和嗜中性粒细胞的活化。因此，在本研究中，我们评估了饮食中的甘氨酸是否可以预防大鼠化学诱导的实验性结肠炎。甘氨酸通过减少结肠组织中炎性细胞因子和趋化因子的诱导来预防TNBS诱导的结肠炎和DSS诱导的结肠炎，这分别代表人克罗恩病和溃疡性结肠炎。据推测，甘氨酸可用于IBD的治疗，其机制涉及调节肠道中的先天免疫系统。

项目成果

Enomoto N, Takei Y, Hirose M, Ikejima K, Kitamura T, Sato N: "Thalidomide prevents alcoholic liver injury in rats through supression of Kupffer cell sensitization and TNF-α production."Gastroenterology. 123. 291-300 (2002)

Enomoto N、Takei Y、Hirose M、Ikejima K、Kitamura T、Sato N：“沙利度胺通过抑制 Kupffer 细胞致敏和 TNF-α 的产生来预防大鼠酒精性肝损伤。”胃肠病学。

Shibuya T, Takei Y, Hirose M, Ikejima K, Enomoto N, Maruyama A, Sato N: "A double-stranded decoy DNA oligomer for NF-κB inhibits TNFα-induced ICAM1 expression in sinusoidal endothelial cells"Biochem.Biophys.Res.Commun.. 298. 10-16 (2002)

Shibuya T、Takei Y、Hirose M、Ikejima K、Enomoto N、Maruyama A、Sato N：“NF-κB 的双链诱饵 DNA 寡聚物抑制正弦内皮细胞中 TNFα 诱导的 ICAM1 表达”Biochem.Biophys.Res。通讯.. 298. 10-16 (2002)

Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei N, Sato N: "Leptin augments inflammatory and profibrogenic responses in the liver induced by acute carbon tetrachloride administration."Hepatology. 34(2). 288-297 (2001)

Ikejima K、Honda H、Yoshikawa M、Hirose M、Kitamura T、Takei N、Sato N：“瘦素增强急性四氯化碳给药诱导的肝脏炎症和促纤维化反应。”肝病学。

Ikejima,K, Honda,H, Yoshikawa,M, Hirose,M, Kitamura,T, Takei,Y, Sato,N: "Leptin augments inflammatory and profibrogenic responses in the liver induced by acute carbon tetrachloride administration."Hepatology. 34(2). 288-297 (2001)

Ikejima,K, Honda,H, Yoshikawa,M, Hirose,M, Kitamura,T, Takei,Y, Sato,N：“瘦素增强急性四氯化碳给药诱导的肝脏炎症和促纤维化反应。”肝病学。

Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Kitamura T, Sato N: "Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat"Gastroenterology. 122. 1399-1410 (2002

Ikejima K、Takei Y、Honda H、Hirose M、Yoshikawa M、Zhang YJ、Lang T、Fukuda T、Kitamura T、Sato N：“瘦素受体介导的信号调节大鼠肝纤维发生和细胞外基质重塑”胃肠病学。