Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
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DOI：
10.1172/jci15841
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
F. Hong;B. Jaruga;Won-Ho Kim;S. Radaeva;O. El-Assal;Z. Tian;V. Nguyen;B. Gao
中科院分区：
文献类型：
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作者：
F. Hong;B. Jaruga;Won-Ho Kim;S. Radaeva;O. El-Assal;Z. Tian;V. Nguyen;B. Gao
T细胞介导的暴发性肝炎是一种危及生命的事件，其潜在机制尚未完全了解。刀豆球蛋白A（Con A）注射到小鼠中再现了T细胞介导的肝炎的组织学和病理学后遗症。在该模型中，信号转导子和转录因子1（STAT 1）和STAT 3的激活子都在肝脏中被激活。通过基因敲除的方式破坏STAT 1基因可减轻肝损伤，抑制CD 4（+）和NK T细胞活化，下调促凋亡干扰素调节因子-1蛋白和细胞因子信号传导抑制因子-1（SOCS 1）的表达，但增强STAT 3活化和STAT 3控制的抗凋亡信号。对IFN-γ缺陷小鼠的研究表明，IFN-γ不仅是负责STAT 1激活的主要细胞因子，而且还部分地负责STAT 3激活。此外，IL-6缺陷小鼠中STAT 3激活的下调与STAT 3控制的抗凋亡信号和SOCS 3表达的减少有关，但与STAT 1激活和STAT 1诱导的促凋亡信号的上调和肝损伤的加重有关。综上所述，这些发现表明，STAT 1通过激活CD 4（+）和NK T细胞并直接诱导肝细胞死亡在Con A介导的肝炎中起有害作用，而STAT 3通过抑制IFN-γ信号传导和诱导抗凋亡蛋白Bcl-X（L）来保护肝损伤。肝细胞中的STAT 1和STAT 3也通过诱导SOCS相互负调节。
T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.