Gut-Derived Lipopolysaccharide Promotes T-Cell-Mediated Hepatitis in Mice through Toll-Like Receptor 4
Gut-Derived Lipopolysaccharide Promotes T-Cell-Mediated Hepatitis in Mice through Toll-Like Receptor 4
复制标题
肠道源性脂多糖通过 Toll 样受体 4 促进小鼠 T 细胞介导的肝炎
DOI：
10.1158/1940-6207.capr-11-0364
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发表时间：
2012-09-01
影响因子：
3.3
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Lin, Yan;Yu, Le-Xing;Wang, Hong-Yang
强有力的临床和流行病学数据支持炎症在肝细胞癌(肝细胞癌)发展中的关键作用。我们以前的数据表明，肠源性脂多糖(LPS)通过激活髓系细胞上表达的Toll样受体4(TLR4)来促进肝癌的发展。然而，肠源性内毒素对其他类型的肝损伤模型的影响还有待研究。本研究的目的是确定肠道来源的内毒素和TLR4信号在模拟病毒性肝炎的T细胞介导的甲型肝炎诱导的肝炎模型中的重要性。应用抗生素方案降低内毒素或基因消融TLR4可显著减轻ConA诱导的小鼠肝损伤，其机制是抑制T淋巴细胞向肝脏的渗入，抑制CD4(+)T淋巴细胞的活化和T辅助细胞1细胞因子的产生；相反，外源性内毒素在体内和体外均能促进ConA诱导的肝炎和CD4(+)T细胞的激活。TLR4基因缺陷小鼠表达TLR4的髓系细胞的重建恢复了ConA诱导的肝损伤和炎症，表明内毒素是主要的细胞靶点。此外，TLR4可能通过穿孔素/颗粒酶B途径正向调节靶细胞的凋亡。提示肠源性内毒素和TLR4在Con A诱导的肝炎中起着重要的积极作用，肠道微生物代谢的调节可能为治疗肝炎病毒感染所致的急性肝炎，从而预防肝细胞癌提供新的途径。癌症前传；5(9)；1090-102。(C)2012年AACR。
Robust clinical and epidemiologic data support the role of inflammation as a key player in hepatocellular carcinoma (HCC) development. Our previous data showed that gut-derived lipopolysaccharide (LPS) promote HCC development by activating Toll-like receptor 4 (TLR4) expressed on myeloid-derived cells. However, the effects of gut-derived LPS on other types of liver injury models are yet to be studied. The purpose of this study was to determine the importance of gut-derived LPS and TLR4 signaling in a T-cell-mediated hepatitis-Con A-induced hepatitis model, which mimic the viral hepatitis. Reduction of endotoxin using antibiotics regimen or genetic ablation of TLR4 in mice significantly alleviate Con A-induced liver injury by inhibiting the infiltration of T lymphocytes into the liver and the activation of CD4(+) T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4(+) T cells activation in vivo and in vitro. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored Con A-induced liver injury and inflammation, indicating the major cell target of LPS. In addition, TLR4 may positively regulate the target hepatocellular apoptosis via the perforin/granzyme B pathway. These data suggest that gut-derived LPS and TLR4 play important positive roles in Con A-induced hepatitis and modulation of the gut microbiotia may represent a new avenue for therapeutic intervention to treat acute hepatitis induced by hepatitis virus infection, thus to prevent hepatocellular carcinoma. Cancer Prev Res; 5(9); 1090-102. (c) 2012 AACR.