TLR4 enhances TGF-beta signaling and hepatic fibrosis.
TLR4 enhances TGF-beta signaling and hepatic fibrosis.
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DOI：
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发表时间：
2007
期刊：
影响因子：
82.9
通讯作者：
E. Seki;S. de Minicis;C. Osterreicher;J. Kluwe;Y. Osawa;D. Brenner;R. Schwabe
中科院分区：
文献类型：
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作者：
E. Seki;S. de Minicis;C. Osterreicher;J. Kluwe;Y. Osawa;D. Brenner;R. Schwabe
肝损伤与肠屏障缺陷和肝脏对细菌产物的暴露增加有关。在这里，我们报告说，肠道细菌菌群和功能性Toll样受体4（TLR 4），而不是TLR 2，是肝纤维化所必需的。使用TLR 4嵌合小鼠和体内脂多糖（LPS）的挑战，我们证明，静止的肝星状细胞（HSC），在肝脏中的肌成纤维细胞的主要前体，是主要的目标，通过TLR 4配体促进纤维化。在静止的HSC中，TLR 4活化不仅上调趋化因子分泌并诱导枯否细胞的趋化性，而且下调转化生长因子（TGF）-β假受体Bambi以使HSC对TGF-β诱导的信号敏感并允许枯否细胞不受限制地活化。LPS诱导的Bambi下调和对TGF-β的敏化是由MyD 88-NF-κ B依赖性途径介导的。因此，Myd 88缺陷型小鼠具有减少的肝纤维化。因此，通过TLR 4-MyD 88-NF-κ B轴调节TGF-β信号提供了促炎信号和促纤维化信号之间的新联系。
Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.