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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / deficiency
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Adaptor Proteins, Vesicular Transport / genetics
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Animals
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Cell Communication / immunology
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Cells, Cultured
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Common Bile Duct / surgery
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Intestinal Mucosa / immunology
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Ligation
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Liver Cirrhosis, Experimental / immunology
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Liver Cirrhosis, Experimental / metabolism*
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Liver Cirrhosis, Experimental / pathology*
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Male
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Myeloid Differentiation Factor 88 / deficiency
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Myeloid Differentiation Factor 88 / genetics
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Signal Transduction* / immunology
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Toll-Like Receptor 2 / physiology
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Toll-Like Receptor 4 / metabolism
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Toll-Like Receptor 4 / physiology*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / physiology*
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Up-Regulation* / immunology
Substances
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Adaptor Proteins, Vesicular Transport
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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TICAM-1 protein, mouse
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Transforming Growth Factor beta