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TLR4 enhances TGF-beta signaling and hepatic fibrosis.

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. 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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Seki E,De Minicis S,Osterreicher CH,Kluwe J,Osawa Y,Brenner DA,Schwabe RF

doi

10.1038/nm1663

subject

Has Abstract

pub_date

2007-11-01 00:00:00

pages

1324-32

issue

11

eissn

1078-8956

issn

1546-170X

pii

nm1663

journal_volume

13

pub_type

杂志文章

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