Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice
Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice
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DOI：
10.1002/hep.21837
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
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作者：
Sakamori, Ryotaro;Takehara, Tetsuo;Hayashi, Norio
脓毒症是一种感染引起的综合征，具有全身性炎症反应，可导致多器官衰竭，偶尔死亡。在此过程中，肝脏中的信号换能器和转录激活因子3 （STAT3）被激活，但该分子的意义尚未确定。我们制造了肝细胞特异性stat3缺陷小鼠（L-STAT3 KO），并检测了这些小鼠对盲肠结扎和穿刺性腹膜炎的易感性，这是一种完善的脓毒症模型。与对照组相比，L-STAT3 KO小鼠的死亡率明显更高，产生的各种急性期蛋白数量也更少。虽然血液细菌感染在L-STAT3 KO小鼠和对照小鼠之间没有差异，但前者表现出全身炎症反应的恶化，各种细胞因子如肿瘤坏死因子α、ifn - γ、IL-6、IL-10、单核细胞趋化蛋白1和巨噬细胞炎症蛋白1 β显著增加。在另一种由脂多糖（LPS）注射引起的脓毒症模型中观察到类似的高炎症反应。体外分析显示，来源于肝细胞并依赖于STAT3的可溶性物质对于抑制lps刺激的巨噬细胞和脾细胞的细胞因子产生至关重要。结论：肝细胞中STAT3的激活可以减轻败血症的全身性高炎症反应和致死率，部分原因是通过抑制免疫细胞的过度激活，这意味着肝细胞STAT3信号在维持宿主稳态中起着关键作用。
Sepsis is an infection-induced syndrome with systemic inflammatory response leading to multiorgan failure and occasionally death. During this process, signal transducer and activator of transcription 3 (STAT3) is activated in the liver, but the significance of this molecule has not been established. We generated hepatocyte-specific STAT3-deficient mice (L-STAT3 KO) and examined the susceptibility of these mice to cecal ligation and puncture-induced peritonitis, a well-established septic model. L-STAT3 KO mice showed significantly higher mortality and produced lesser amounts of various acute phase proteins than control littermates. Although blood bacterial infection did not differ between L-STAT3 KO mice and control mice, the former showed deterioration of the systemic inflammatory response as evidenced by a significant increase in various cytokines such as tumor necrosis factor alpha, IFN-gamma, IL-6, IL-10, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1 beta. A similar hyperinflammatory response was observed in another septic model caused by lipopolysaccharide (LPS) injection. In vitro analysis revealed that soluble substances derived from hepatocytes and dependent on STAT3 were critical for suppression of cytokine production from LPS-stimulated macrophage and splenocytes. Conclusion: STAT3 activation in hepatocytes can attenuate a systemic hyperinflammatory response and lethality in sepsis, in part by suppressing immune cell overactivation, implying a critical role of hepatocyte STAT3 signaling in maintaining host homeostasis.