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. 2007 Nov;13(11):1324-32.
doi: 10.1038/nm1663. Epub 2007 Oct 21.

TLR4 enhances TGF-beta signaling and hepatic fibrosis (V体育ios版)

Ekihiro Seki  1 , Samuele De Minicis, Christoph H Osterreicher, Johannes Kluwe, Yosuke Osawa, David A Brenner, Robert F Schwabe
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TLR4 enhances TGF-beta signaling and hepatic fibrosis

Ekihiro Seki et al. Nat Med. 2007 Nov.

Abstract

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 VSports手机版. 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. .

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