CCAAT Enhancer-binding Protein (cid:1) Is Required for Interleukin-6 Receptor (cid:1) Signaling in Newborn Hepatocytes*
CCAAT Enhancer-binding Protein (cid:1) Is Required for Interleukin-6 Receptor (cid:1) Signaling in Newborn Hepatocytes*
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CCAAT 增强子结合蛋白 (cid:1) 是新生肝细胞中白细胞介素 6 受体 (cid:1) 信号传导所必需的*
DOI：
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
G. Darlington
中科院分区：
文献类型：
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作者：
S. Mackey;G. Darlington
急性期反应是肝脏对炎症刺激的进化保守反应，其帮助机体进行宿主防御和稳态。我们以前曾报道，CCAAT增强子结合蛋白（cid：1）（C/EBP（cid：1））是所需的诱导急性时相蛋白（APP）基因在新生小鼠响应脂多糖。在本文中，我们描述了一种机制，C/EBP（cid：1）基因敲除小鼠不能诱导APP基因表达的炎症刺激。我们证明了C/EBP（cid：1）基因敲除小鼠缺乏急性期反应是因为肝细胞自主缺陷。C/EBP（cid：1）敲除肝细胞对重组白细胞介素（IL）-6应答时不激活STAT 3，表明IL-6通路中存在缺陷。C/EBP（cid：1）敲除肝细胞也未显示其他IL-6受体（IL-6 R）介导的Janus激酶底物gp 130、SHP-2和Tyk 2的活化。对IL-6通路的进一步检查表明，C/EBP（cid：1）敲除肝细胞具有降低的IL-6 R（cid：1）蛋白水平，部分原因是蛋白稳定性降低。然而，IL-6途径的其他组分是完整的，如用重组可溶性IL-6 R拯救STAT 3活化和APP基因诱导所证明的。
The acute phase response is an evolutionarily conserved response of the liver to inflammatory stimuli, which aids the body in host defense and homeostasis. We have previously reported that CCAAT enhancer-binding protein (cid:1) (C/EBP (cid:1) ) is required for the induction of acute phase protein (APP) genes in newborn mice in response to lipopolysaccharide. In this paper, we describe a mechanism by which C/EBP (cid:1) knock-out mice are unable to induce APP gene expression in response to inflammatory stimuli. We demonstrate that the lack of acute phase response in C/EBP (cid:1) knock-out mice is because of a hepatocyte autonomous defect. C/EBP (cid:1) knock-out hepatocytes do not activate STAT3 in response to recombinant interleukin (IL)-6, indicating a defect in the IL-6 pathway. C/EBP (cid:1) knock-out hepatocytes also do not show activation of other IL-6 receptor (IL-6R)-mediated Janus kinase substrates, gp130, SHP-2, and Tyk2. Further examination of the IL-6 pathway demonstrated that C/EBP (cid:1) knock-out hepatocytes have decreased IL-6R (cid:1) protein levels caused, in part, by reduced protein stability. However, other components of the IL-6 pathway are intact, as demonstrated by rescue of STAT3 activation and APP gene induction with recombinant-soluble IL-6R