{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:45:41Z","timestamp":1791089141823,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2013,3,1]],"date-time":"2013-03-01T00:00:00Z","timestamp":1362096000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2013,2,28]],"date-time":"2013-02-28T00:00:00Z","timestamp":1362009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Toll-like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of nonparenchymal liver cells. The fibrogenic signaling events downstream of TLRs on Kupffer cells (KCs) and hepatic stellate cells (HSCs) are poorly defined. Here, we describe the MAP3K tumor progression locus 2 (Tpl2) as being important for the activation of extracellular regulated kinase (ERK) signaling in KCs and HSCs responding to stimulation of TLR4 and TLR9. KCs lacking Tpl2 display defects with TLR induction of cytokines interleukin (IL)-1\u03b2, IL-10, and IL-23.<\/jats:bold>\n                                 <jats:bold>\n                                    tpl2\n                                 <\/jats:bold>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup>\n                                 <jats:bold>HSCs were unable to increase expression of fibrogenic genes IL-1\u03b2 and tissue inhibitor of metalloproteinase 1 (TIMP-1), with the latter being the result of defective stimulation of TIMP-1 promoter activity by TLRs. To determine the<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>relevance of Tpl2 signaling in liver fibrosis, we compared the fibrogenic responses of wild-type (WT) and<\/jats:bold>\n                                 <jats:bold>\n                                    tpl2\n                                 <\/jats:bold>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup>\n                                 <jats:bold>mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine-choline\u2013deficient diet models, we observed a significant reduction in fibrosis in mice lacking Tpl2, compared to WT controls. However, in the bile duct ligation model, there was no effect of<\/jats:bold>\n                                 <jats:bold>\n                                    tpl2\n                                 <\/jats:bold>\n                                 <jats:bold>deletion, which may reflect a lesser role for HSCs in wounding response to biliary injury.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>: <jats:bold>We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KCs and HSCs by the ERK pathway and that suppression of its catalytic activity may be a route toward suppressing fibrosis caused by hepatocellular injuries. (Hepatology 2013)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26108","type":"journal-article","created":{"date-parts":[[2012,10,18]],"date-time":"2012-10-18T19:29:49Z","timestamp":1350588589000},"page":"1238-1249","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":41,"title":["Tumor progression locus 2\/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor\u2013induced TIMP-1 gene transcription in hepatic stellate cells in mice"],"prefix":"10.1097","volume":"57","author":[{"given":"Maria J.","family":"Perugorria","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay 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protean, multifunctional, and enigmatic cells of the liver.","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol Rev"},{"key":"R6-43-20241201","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.jhep.2007.02.003","article-title":"Expression of MMPs and TIMPs in liver fibrosisa systematic review with special emphasis on antifibrotic strategies.","volume":"46","author":"Hemmann","year":"2007","journal-title":"J Hepatol"},{"key":"R7-43-20241201","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1053\/j.gastro.2006.01.038","article-title":"Tolllike receptor signaling in the liver.","volume":"130","author":"Schwabe","year":"2006","journal-title":"Gastroenterology"},{"key":"R8-43-20241201","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.22034","article-title":"Liver: an organ with predominant innate 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