Fas ligand is responsible for CXCR3 chemokine induction in CD4+ T cell-dependent liver damage
Fas ligand is responsible for CXCR3 chemokine induction in CD4+ T cell-dependent liver damage
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DOI：
10.4049/jimmunol.176.10.6235
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发表时间：
2006-05-15
影响因子：
4.4
通讯作者：
Hahn, Young S.
中科院分区：
文献类型：
--
作者：
Cruise, Michael W.;Lukens, John R.;Hahn, Young S.
免疫介导的肝损伤已被证明在丙型肝炎病毒（HCV）和其他嗜肝感染的发病机制。Fas/Fas配体（FasL）相互作用在免疫介导的肝损伤中起重要作用。为了了解FasL介导的肝脏炎症的分子机制，我们通过分析HCV核心x TCR（DO11.10）双转基因小鼠中趋化因子和趋化因子受体的表达，研究了表达高水平FasL的CD 4（+）T细胞对肝损伤起始的影响。体内抗原刺激触发核心表达Ag特异性CD 4（+）T细胞显著流入免疫的核心（+）TCR小鼠的肝脏，但不是它们的核心（-）TCR同窝出生的小鼠。引人注目的是，核心（+）TCR小鼠肝脏中的炎症过程伴随着IFN-γ产生诱导的IFN-诱导蛋白10和单核因子的急剧增加。肝内淋巴细胞主要为CXCR 3阳性，抗CXCR 3 Ab治疗可消除CXCR 3（+）淋巴细胞向肝脏的迁移和肝损伤。重要的是，Fas/FasL相互作用的阻断降低了IFN-γ诱导的IFN-诱导蛋白10和单核因子的表达以及细胞浸润到肝脏中。这些结果表明，活化的CD 4（+）T细胞与FasL表达升高参与促进肝脏炎症和肝损伤，通过诱导趋化因子。
Immune-mediated hepatic damage has been demonstrated in the pathogenesis of hepatitis C virus (HCV) and other hepatotrophic infections. Fas/Fas ligand (FasL) interaction plays a critical role in immune-mediated hepatic damage. To understand the molecular mechanism(s) of FasL-mediated liver inflammation, we examined the effect of CD4(+) T cells expressing high levels of FasL on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression in HCV core x TCR (DO11.10) double-transgenic mice. In vivo antigenic stimulation triggers a marked influx of core-expressing Ag-specific CD4(+) T cells into the liver of the immunized core(+) TCR mice but not their core(-) TCR littermates. Strikingly, the inflammatory process in the liver of core(+) TCR mice was accompanied by a dramatic increase in IFN-inducible protein 10 and monokine induced by IFN-gamma production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 Ab treatment abrogates migration of CXCR3(+) lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IFN-inducible protein 10 and monokine induced by IFN-gamma and cellular infiltration into the liver. These findings suggest that activated CD4(+) T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.