STAT4 knockout mice are more susceptible to concanavalin A-induced T-cell hepatitis.
STAT4 knockout mice are more susceptible to concanavalin A-induced T-cell hepatitis.
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DOI：
10.1016/j.ajpath.2014.02.023
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发表时间：
2014-06
期刊：
影响因子：
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通讯作者：
Yan Wang;D. Feng;Hua Wang;Ming-Jiang Xu;Ogyi Park;Yongmei Li;B. Gao
中科院分区：
文献类型：
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作者：
Yan Wang;D. Feng;Hua Wang;Ming-Jiang Xu;Ogyi Park;Yongmei Li;B. Gao
主要由IL-12激活的STAT 4通过诱导Th 1和Th 2细胞因子促进炎症反应。最近的全基因组关联研究表明，STAT 4基因变异与多种类型肝病的风险相关，但STAT 4如何参与肝病的发病机制尚不清楚。在这项研究中，在病毒性肝炎和自身免疫性肝炎患者的肝脏免疫细胞中以及刀豆球蛋白A（Con A）诱导的肝炎小鼠模型中检测到STAT 4激活。这种STAT 4激活主要在T细胞、自然杀伤T细胞、巨噬细胞和枯否细胞中检测到，在Il 12 a −/−和Il 12 b −/−小鼠中减少。正如预期的那样，Stat 4基因的破坏减少了Th 1和Th 2细胞因子的产生，但令人惊讶地加剧了Con A诱导的肝损伤。同样地，破坏IL 12和IL 12 b也增加了Con A诱导的肝细胞损伤。进一步的研究表明，来自ConA处理的Stat 4 −/−小鼠的肝自然杀伤T（NKT）细胞比来自ConA处理的WT小鼠的肝自然杀伤T细胞具有更高水平的FasL表达和更强的对肝细胞的细胞毒性。总之，尽管上调促炎细胞因子，STAT 4保护免受急性T细胞肝炎，这是通过直接或间接下调NKT细胞上的FasL表达介导的。
STAT4, which is activated mainly by IL-12, promotes inflammatory responses by inducing Th1 and Th2 cytokines. Recent genome-wide association studies indicate thatSTAT4gene variants are associated with risk of various types of liver diseases, but how STAT4 contributes to liver disease pathogenesis remains obscure. In this study, STAT4 activation was detected in liver immune cells from patients with viral hepatitis and autoimmune hepatitis, as well as in a mouse model of concanavalin A (Con A)–induced hepatitis. Such STAT4 activation was detected mainly in T cells, natural killer T cells, and macrophages and Kupffer cells, and was diminished inIl12a−/−andIl12b−/−mice. As expected, disruption of theStat4gene reduced production of Th1 and Th2 cytokines, but surprisingly exacerbated Con A–induced liver injury. Similarly, disruption ofIl12aorIl12balso augmented Con A–induced hepatocellular damage. Further studies showed that hepatic natural killer T (NKT) cells from Con A–treatedStat4−/−mice had higher levels of FasL expression and increased cytotoxicity against hepatocytes than those from Con A–treated WT mice.In vitro, blocking FasL attenuatedStat4−/−NKT cytotoxicity against hepatocytes. In conclusion, despite up-regulation of proinflammatory cytokines, STAT4 protects against acute T-cell hepatitis, which is mediated by direct or indirect down-regulation of FasL expression on NKT cells.