Article abstract
Nature Medicine 13, 1324 - 1332 (2007)
Published online: 21 October 2007 | doi:10.1038/nm1663
TLR4 enhances TGF-
signaling and hepatic fibrosis
Ekihiro Seki1,2, Samuele De Minicis1,2, Christoph H Österreicher1,2, Johannes Kluwe1, Yosuke Osawa1, David A Brenner2 & Robert F Schwabe1
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)-
pseudoreceptor Bambi to sensitize HSCs to TGF-–induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF- is mediated by a MyD88–NF-
B–dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF- signaling by a TLR4-MyD88–NF-B axis provides a novel link between proinflammatory and profibrogenic signals.
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093, USA.
Correspondence to: Robert F Schwabe1 e-mail: rfs2102@columbia.edu
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