Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity
Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity
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DOI：
10.4049/jimmunol.178.6.3777
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Matsukawa, Akihiro
中科院分区：
文献类型：
--
作者：
Numata, Kosuke;Kubo, Masato;Matsukawa, Akihiro
细胞因子参与了对乙酰氨基酚(APAP)诱导的急性肝损伤的进展。细胞因子信号转导抑制因子(SOCS)蛋白通过抑制JAK-STAT通路对细胞因子信号转导起负调节作用，但它们在APAP肝毒性中的作用尚不清楚。在本研究中，我们试图探讨SOCS3在APAP诱导的肝损伤中的作用。与野生型小鼠相比，在T细胞中存在SOCS3细胞特异性过表达的小鼠(SOCS3Tg，其中TG是转基因的)在APAP攻击后表现出严重的肝损伤，表现为血清丙氨酸转氨酶水平升高，肝脏坏死加剧，存活率下降。适应性地将SOCS3Tg-CD4(+)T细胞转移到T和B细胞缺陷RAG-2(-/-)小鼠体内，与对照组相比，导致了肝损伤的加重。在SOCS3Tg小鼠中，随着抗凋亡蛋白bcl2表达的减少，肝细胞凋亡增加，而细胞周期调节蛋白的改变则抑制了肝细胞的增殖。与对照组相比，SOCS3Tg组小鼠循环中的干扰素-γ和肿瘤坏死因子-α水平升高。使用中和抗体的研究表明，升高的干扰素-γ和肿瘤坏死因子-α是导致SOCS3Tg小鼠肝脏毒性加重的原因。在SOCS3Tg肝细胞中，对肝损伤有害的他汀类药物的激活增强。或者，在SOCS3Tg肝细胞中，保护肝脏的STAT3活性降低，这一事件与肝细胞中SOCS3表达增强有关。综上所述，这些结果表明，在APAP肝毒性中，强迫表达SOCS3是有害的，因为它增加了肝细胞中STAT1的激活，而降低了肝细胞中的STAT3的激活，这可能是通过升高干扰素-γ和肿瘤坏死因子-α来实现的。
Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4(+) T cells into T and B cell-deficient RAG-2(-/-) mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STATl that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-gamma and TNF-alpha.