Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings
Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings
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DOI：
10.1016/j.jhep.2007.08.020
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发表时间：
2008-02-01
影响因子：
25.7
通讯作者：
Nakanishi, Kenji
中科院分区：
文献类型：
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作者：
Seki, Ekihiro;Kondo, Yuichi;Nakanishi, Kenji
背景/目标：由于stat 3的条件性敲除小鼠在部分肝切除术后肝再生受损，而gp 130的小鼠在早期STAT 3磷酸化中有缺陷，但具有正常的DNA合成，独立于gp 130诱导的晚期STAT 3磷酸化似乎对肝再生至关重要。由于HGF和EGF可以分别通过gp 130非依赖性MET和EGFR激活STAT 3，因此我们假设这些因素可以解释STAT 3依赖性肝再生。在此，我们通过在肝细胞中选择性地引入细胞因子信号转导抑制因子（SOCS）-1和SOCS 3（STAT 3信号转导的有效负调节因子）来研究这一假说。方法：我们制备了表达socs 1和socs 3的重组腺病毒。感染socs 1-病毒的肝细胞缺乏对IL-6和HGF的应答的STAT 3磷酸化，而感染socs 3-病毒的细胞缺乏对所有IL-6的应答，HGF和EGF，表明这些SOCS蛋白不同地调节EGFR信号传导。感染socs 3病毒的小鼠表现出严重的和持续的损害，而那些与socs 1病毒只表现出延迟再生，表明MET和EGFR signalings.Conclusions的要求：这些结果清楚地表明，MET和EGFR介导的STAT 3信号合作有助于肝再生，并可以提供新的见解组织内稳态。(c)2007年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes.Methods: We generated recombinant adenoviruses expressing socs1 and socs3.Results: Hepatocytes infected with socs1-virus lacked STAT3 phosphorylation in response to IL-6 and HGF, while cells infected with socs3-virus lacked the response to all of IL-6, HGF and EGF, indicating that those SOCS proteins differently regulate EGFR signaling. Mice infected with socs3-virus exhibited severe and persistent impairment while those with socs1-virus showed only delayed regeneration, indicating requirement of both MET and EGFR signalings.Conclusions: These results clearly demonstrated that MET- and EGFR-mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.