TLR4 enhances TGF-beta signaling and hepatic fibrosis Export

@article{Seki:2007p534, 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.}, author = {Seki, Ekihiro and De Minicis, Samuele and Osterreicher, Christoph H. and Kluwe, Johannes and Osawa, Yosuke and Brenner, David A. and Schwabe, Robert F.}, citeulike-article-id = {3046183}, citeulike-linkout-0 = {http://www.nature.com/nm/journal/v13/n11/abs/nm1663.html;jsessionid=66C8C1557E1D2FB90A213F4867C4E70B}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nm1663}, doi = {10.1038/nm1663}, journal = {Nat Med}, keywords = {2, 4, 88, adaptor, animals, beta, bile, c3h, c57bl, cell, cells, cirrhosis, common, communication, cultured, differentiation, duct, experimental, factor, file-import-08-07-27, growth, inbred, intestinal, knockout, ligation, liver, male, mice, mucosa, myeloid, proteins, receptor, signal, toll-like, transduction, transforming, transgenic, transport, up-regulation, vesicular}, local-url = {file://localhost/Users/ken/Documents/Papers/2007/Seki/Nat\%20Med\%202007\%20Seki.pdf}, month = {Nov}, number = {11}, pages = {1324--32}, posted-at = {2008-07-27 14:46:01}, priority = {2}, title = {TLR4 enhances TGF-beta signaling and hepatic fibrosis}, url = {http://dx.doi.org/10.1038/nm1663}, volume = {13}, year = {2007} }

TY - JOUR ID - Seki:2007p534 L3 - citeulike-article-id:3046183 N2 - 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. IS - 11 JF - Nat Med EP - 32 TI - TLR4 enhances TGF-beta signaling and hepatic fibrosis VL - 13 SP - 1324 KW - 2 KW - 4 KW - 88 KW - adaptor KW - animals KW - beta KW - bile KW - c3h KW - c57bl KW - cell KW - cells KW - cirrhosis KW - common KW - communication KW - cultured KW - differentiation KW - duct KW - experimental KW - factor KW - file-import-08-07-27 KW - growth KW - inbred KW - intestinal KW - knockout KW - ligation KW - liver KW - male KW - mice KW - mucosa KW - myeloid KW - proteins KW - receptor KW - signal KW - toll-like KW - transduction KW - transforming KW - transgenic KW - transport KW - up-regulation KW - vesicular AU - Seki, Ekihiro AU - De Minicis, Samuele AU - Osterreicher, Christoph AU - Kluwe, Johannes AU - Osawa, Yosuke AU - Brenner, David AU - Schwabe, Robert PY - 2007/Nov// UR - http://dx.doi.org/10.1038/nm1663 ER -