Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-κB-independent, caspase-3-dependent pathway
Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-κB-independent, caspase-3-dependent pathway
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DOI：
10.1074/jbc.m109791200
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发表时间：
2001-12-28
影响因子：
4.8
通讯作者：
Maher, JJ
中科院分区：
文献类型：
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作者：
Faouzi, S;Burckhardt, BE;Maher, JJ
当在体内给予小鼠时，针对Fas受体的激动性抗体在肝脏中引起显著的细胞凋亡。在这项研究中，我们发现抗Fas抗体不仅导致肝细胞凋亡，而且还引起肝脏炎症。注射抗Fas抗体后2小时，当小鼠显示caspase-3活化和凋亡的证据时，我们发现CXC趋化因子巨噬细胞炎性蛋白-2和KC的显著肝诱导。与趋化因子诱导相一致的是中性粒细胞对肝实质的浸润。中和实验表明，趋化因子是Fas诱导的肝脏炎症的原因，KC具有主导作用。抗Fas处理小鼠肝脏中的趋化因子诱导与NF-κ B活化无关。相反，它与激活蛋白-1（AP-1）的核转位相一致。在抗Fas处理后1-2小时检测到肝脏中的AP-1活化，表明与细胞凋亡的发生有关。当细胞凋亡被caspase-3抑制剂预处理小鼠，AP-1激活和肝趋化因子的生产都显着减少。肝脏炎症也减少了70%。总之，这些发现表明Fas连接可以在体内诱导肝脏炎症。炎症不是由Fas介导的通过NF-κ B的信号传导引起的;相反，它代表了一种间接作用，需要激活caspase-3和AP-1的核转位。
Agonistic antibodies against the Fas receptor, when administered to mice in vivo, cause significant apoptosis in the liver. In this study we show that anti-Fas antibody not only causes apoptosis of liver cells but also provokes hepatic inflammation. Two hours after injection of anti-Fas, when mice displayed evidence of caspase-3 activation and apoptosis, we found significant hepatic induction of the CXC chemokines macrophage inflammatory protein-2 and KC. Coincident with the chemokine induction was infiltration of the hepatic parenchyma by neutrophils. Neutralization experiments identified that chemokines were the cause of Fas-induced hepatic inflammation, with KC having the predominant effect. Chemokine induction in the livers of anti-Fas-treated mice was not associated with activation of NF-kappaB. Instead, it coincided with nuclear translocation of activator protein-1 (AP-1). AP-1 activation in liver was detected 1-2 h after anti-Fas treatment, suggesting a connection to the onset of apoptosis. When apoptosis was prevented by pretreating mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced. Hepatic inflammation was also reduced by 70%. Taken together, these findings indicate that Fas ligation can induce inflammation in the liver in vivo. Inflammation does not arise from Fas-mediated signaling through NF-kappaB; rather, it represents an indirect effect, requiring activation of caspase-3 and nuclear translocation of AP-1.