{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:51:17Z","timestamp":1791093077445,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Biosci"],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Tissue inhibitor of metalloproteinase 1 (TIMP-1), which is thought to be produced mainly by activated hepatic stellate cells and Kupffer cells in the liver, plays a pivotal role in matrix remodeling during liver injury and repair; while the effect of TIMP-1 on hepatocellular damage remains obscure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatic expression of TIMP-1 mRNA and protein was up-regulated both in acute and chronic liver injury induced by carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>). Compared with wild-type mice, TIMP-1 knockout mice were more susceptible to CCl<jats:sub>4<\/jats:sub>-induced acute and chronic liver injury, as shown by higher levels of serum alanine aminotransferase (ALT), greater number of apoptotic hepatocytes, and more extended necroinflammatory foci. TIMP-1 knockout mice also displayed greater degree of liver fibrosis after chronic CCl<jats:sub>4<\/jats:sub>injection when compared with wild-type mice.<jats:italic>In vitro<\/jats:italic>treatment with TIMP-1 inhibited cycloheximide-induced cell death of primary mouse hepatocytes. Finally, up-regulation of TIMP-1 in the liver and serum after chronic CCl<jats:sub>4<\/jats:sub>treatment was markedly diminished in hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) knockout mice.<jats:italic>In vitro<\/jats:italic>treatment with interleukin-6 stimulated TIMP-1 production in primary mouse hepatocytes, but to a lesser extent in STAT3-deficient hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>TIMP-1 plays an important role in protecting against acute and chronic liver injury and subsequently inhibiting liver fibrosis induced by CCl<jats:sub>4<\/jats:sub>. In addition to activated stellate cells and Kupffer cells, hepatocytes are also responsible for TIMP-1 production during liver injury via a STAT3-dependent manner.<\/jats:p><\/jats:sec>","DOI":"10.1186\/2045-3701-1-14","type":"journal-article","created":{"date-parts":[[2011,4,6]],"date-time":"2011-04-06T19:43:13Z","timestamp":1302118993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP-1 production"],"prefix":"10.1186","volume":"1","author":[{"given":"Hua","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fouad","family":"Lafdil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechun","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,4,4]]},"reference":[{"key":"14_CR1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nrgastro.2010.97","volume":"7","author":"SL Friedman","year":"2010","unstructured":"Friedman SL: Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010, 7: 425-436. 10.1038\/nrgastro.2010.97","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"14_CR2","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1152\/physrev.00061.2009","volume":"90","author":"H Malhi","year":"2010","unstructured":"Malhi H, Guicciardi ME, Gores GJ: Hepatocyte death: a clear and present danger. Physiol Rev. 2010, 90: 1165-1194. 10.1152\/physrev.00061.2009","journal-title":"Physiol Rev"},{"key":"14_CR3","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2353\/ajpath.2010.090675","volume":"176","author":"GK Michalopoulos","year":"2010","unstructured":"Michalopoulos GK: Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010, 176: 2-13. 10.2353\/ajpath.2010.090675","journal-title":"Am J Pathol"},{"key":"14_CR4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1055\/s-2006-927388","volume":"45","author":"M Roderfeld","year":"2007","unstructured":"Roderfeld M, Hemmann S, Roeb E: Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs). Z Gastroenterol. 2007, 45: 25-33. 10.1055\/s-2006-927388","journal-title":"Z Gastroenterol"},{"key":"14_CR5","first-page":"143","volume":"24","author":"M Consolo","year":"2009","unstructured":"Consolo M, Amoroso A, Spandidos DA, Mazzarino MC: Matrix metalloproteinases and their inhibitors as markers of inflammation and fibrosis in chronic liver disease (Review). Int J Mol Med. 2009, 24: 143-152.","journal-title":"Int J Mol Med"},{"key":"14_CR6","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/hep.20618","volume":"41","author":"FF Mohammed","year":"2005","unstructured":"Mohammed FF, Pennington CJ, Kassiri Z, Rubin JS, Soloway PD, Ruther U: Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. Hepatology. 2005, 41: 857-867. 10.1002\/hep.20618","journal-title":"Hepatology"},{"key":"14_CR7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.semcdb.2007.07.003","volume":"19","author":"AM Manicone","year":"2008","unstructured":"Manicone AM, McGuire JK: Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008, 19: 34-41. 10.1016\/j.semcdb.2007.07.003","journal-title":"Semin Cell Dev Biol"},{"key":"14_CR8","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.jhep.2007.02.003","volume":"46","author":"S Hemmann","year":"2007","unstructured":"Hemmann S, Graf J, Roderfeld M, Roeb E: Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol. 2007, 46: 955-975. 10.1016\/j.jhep.2007.02.003","journal-title":"J Hepatol"},{"key":"14_CR9","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","volume":"141","author":"K Kessenbrock","year":"2010","unstructured":"Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010, 141: 52-67. 10.1016\/j.cell.2010.03.015","journal-title":"Cell"},{"key":"14_CR10","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1002\/hep.23754","volume":"52","author":"A Dechene","year":"2010","unstructured":"Dechene A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP, El Fouly A: Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology. 2010, 52: 1008-1016. 10.1002\/hep.23754","journal-title":"Hepatology"},{"key":"14_CR11","doi-asserted-by":"publisher","first-page":"3955","DOI":"10.4049\/jimmunol.0903008","volume":"184","author":"SK Madala","year":"2010","unstructured":"Madala SK, Pesce JT, Ramalingam TR, Wilson MS, Minnicozzi S, Cheever AW: Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis. J Immunol. 2010, 184: 3955-3963. 10.4049\/jimmunol.0903008","journal-title":"J Immunol"},{"key":"14_CR12","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/hep.21929","volume":"47","author":"V Defamie","year":"2008","unstructured":"Defamie V, Laurens M, Patrono D, Devel L, Brault A, Saint-Paul MC: Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury. Hepatology. 2008, 47: 177-185. 10.1002\/hep.21929","journal-title":"Hepatology"},{"key":"14_CR13","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1007\/s10555-006-7893-x","volume":"25","author":"R Chirco","year":"2006","unstructured":"Chirco R, Liu XW, Jung KK, Kim HR: Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev. 2006, 25: 99-113. 10.1007\/s10555-006-7893-x","journal-title":"Cancer Metastasis Rev"},{"key":"14_CR14","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1053\/j.gastro.2008.09.013","volume":"136","author":"V Nobili","year":"2009","unstructured":"Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D: Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009, 136: 160-167. 10.1053\/j.gastro.2008.09.013","journal-title":"Gastroenterology"},{"key":"14_CR15","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1002\/hep.20425","volume":"40","author":"CJ Parsons","year":"2004","unstructured":"Parsons CJ, Bradford BU, Pan CQ, Cheung E, Schauer M, Knorr A: Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. Hepatology. 2004, 40: 1106-1115. 10.1002\/hep.20425","journal-title":"Hepatology"},{"key":"14_CR16","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1053\/jhep.2002.35625","volume":"36","author":"H Yoshiji","year":"2002","unstructured":"Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T: Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology. 2002, 36: 850-860.","journal-title":"Hepatology"},{"key":"14_CR17","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.cld.2008.07.001","volume":"12","author":"RG Gieling","year":"2008","unstructured":"Gieling RG, Burt AD, Mann DA: Fibrosis and cirrhosis reversibility - molecular mechanisms. Clin Liver Dis. 2008, 12: 915-937. xi. 10.1016\/j.cld.2008.07.001","journal-title":"Clin Liver Dis"},{"key":"14_CR18","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","volume":"134","author":"SL Friedman","year":"2008","unstructured":"Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008, 134: 1655-1669. 10.1053\/j.gastro.2008.03.003","journal-title":"Gastroenterology"},{"key":"14_CR19","doi-asserted-by":"publisher","first-page":"11069","DOI":"10.1074\/jbc.M111490200","volume":"277","author":"FR Murphy","year":"2002","unstructured":"Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ: Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem. 2002, 277: 11069-11076. 10.1074\/jbc.M111490200","journal-title":"J Biol Chem"},{"key":"14_CR20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S1357-2725(96)00118-5","volume":"29","author":"JP Iredale","year":"1997","unstructured":"Iredale JP: Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol. 1997, 29: 43-54. 10.1016\/S1357-2725(96)00118-5","journal-title":"Int J Biochem Cell Biol"},{"key":"14_CR21","first-page":"3517","volume":"26","author":"WI Jeong","year":"2006","unstructured":"Jeong WI, Do SH, Jeong DH, Hong IH, Park JK, Ran KM: Kinetics of MMP-1 and MMP-3 produced by mast cells and macrophages in liver fibrogenesis of rat. Anticancer Res. 2006, 26: 3517-3526.","journal-title":"Anticancer Res"},{"key":"14_CR22","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1002\/hep.1840180624","volume":"18","author":"E Roeb","year":"1993","unstructured":"Roeb E, Graeve L, Hoffmann R, Decker K, Edwards DR, Heinrich PC: Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures. Hepatology. 1993, 18: 1437-1442. 10.1002\/hep.1840180624","journal-title":"Hepatology"},{"key":"14_CR23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0014-5793(94)00636-9","volume":"349","author":"E Roeb","year":"1994","unstructured":"Roeb E, Graeve L, Mullberg J, Matern S, Rose-John S: TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes. FEBS Lett. 1994, 349: 45-49. 10.1016\/0014-5793(94)00636-9","journal-title":"FEBS Lett"},{"key":"14_CR24","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1002\/hep.510290333","volume":"29","author":"MJ Bahr","year":"1999","unstructured":"Bahr MJ, Vincent KJ, Arthur MJ, Fowler AV, Smart DE, Wright MC: Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: regulation by activator protein-1 DNA binding proteins. Hepatology. 1999, 29: 839-848. 10.1002\/hep.510290333","journal-title":"Hepatology"},{"key":"14_CR25","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1053\/jhep.2001.22520","volume":"33","author":"N Nieto","year":"2001","unstructured":"Nieto N, Dominguez-Rosales JA, Fontana L, Salazar A, Armendariz-Borunda J, Greenwel P: Rat hepatic stellate cells contribute to the acute-phase response with increased expression of alpha1(I) and alpha1(IV) collagens, tissue inhibitor of metalloproteinase-1, and matrix-metalloproteinase-2 messenger RNAs. Hepatology. 2001, 33: 597-607. 10.1053\/jhep.2001.22520","journal-title":"Hepatology"},{"key":"14_CR26","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1002\/hep.21427","volume":"44","author":"N Nieto","year":"2006","unstructured":"Nieto N: Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells. Hepatology. 2006, 44: 1487-1501. 10.1002\/hep.21427","journal-title":"Hepatology"},{"key":"14_CR27","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.1093\/nar\/23.24.5041","volume":"23","author":"M Bugno","year":"1995","unstructured":"Bugno M, Graeve L, Gatsios P, Koj A, Heinrich PC, Travis J: Identification of the interleukin-6\/oncostatin M response element in the rat tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. Nucleic Acids Res. 1995, 23: 5041-5047. 10.1093\/nar\/23.24.5041","journal-title":"Nucleic Acids Res"},{"key":"14_CR28","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1016\/j.bbrc.2003.11.050","volume":"312","author":"SJ Lee","year":"2003","unstructured":"Lee SJ, Yoo HJ, Bae YS, Kim HJ, Lee ST: TIMP-1 inhibits apoptosis in breast carcinoma cells via a pathway involving pertussis toxin-sensitive G protein and c-Src. Biochem Biophys Res Commun. 2003, 312: 1196-1201. 10.1016\/j.bbrc.2003.11.050","journal-title":"Biochem Biophys Res Commun"},{"key":"14_CR29","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.4049\/jimmunol.159.5.2431","volume":"159","author":"CD Richards","year":"1997","unstructured":"Richards CD, Kerr C, Tanaka M, Hara T, Miyajima A, Pennica D: Regulation of tissue inhibitor of metalloproteinase-1 in fibroblasts and acute phase proteins in hepatocytes in vitro by mouse oncostatin M, cardiotrophin-1, and IL-6. J Immunol. 1997, 159: 2431-2437.","journal-title":"J Immunol"},{"key":"14_CR30","doi-asserted-by":"publisher","first-page":"3376","DOI":"10.1210\/me.2006-0177","volume":"20","author":"S Lin","year":"2006","unstructured":"Lin S, Saxena NK, Ding X, Stein LL, Anania FA: Leptin increases tissue inhibitor of metalloproteinase I (TIMP-1) gene expression by a specificity protein 1\/signal transducer and activator of transcription 3 mechanism. Mol Endocrinol. 2006, 20: 3376-3388. 10.1210\/me.2006-0177","journal-title":"Mol Endocrinol"},{"key":"14_CR31","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1053\/j.gastro.2008.01.016","volume":"134","author":"N Horiguchi","year":"2008","unstructured":"Horiguchi N, Wang L, Mukhopadhyay P, Park O, Jeong WI, Lafdil F: Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology. 2008, 134: 1148-1158. 10.1053\/j.gastro.2008.01.016","journal-title":"Gastroenterology"},{"key":"14_CR32","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1053\/j.gastro.2007.09.034","volume":"134","author":"WI Jeong","year":"2008","unstructured":"Jeong WI, Park O, Gao B: Abrogation of the antifibrotic effects of natural killer cells\/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology. 2008, 134: 248-258. 10.1053\/j.gastro.2007.09.034","journal-title":"Gastroenterology"}],"container-title":["Cell &amp; Bioscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/2045-3701-1-14.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T04:38:19Z","timestamp":1686026299000},"score":1,"resource":{"primary":{"URL":"https:\/\/cellandbioscience.biomedcentral.com\/articles\/10.1186\/2045-3701-1-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,4]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,4]]}},"alternative-id":["14"],"URL":"https:\/\/doi.org\/10.1186\/2045-3701-1-14","relation":{},"ISSN":["2045-3701"],"issn-type":[{"value":"2045-3701","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,4]]},"assertion":[{"value":"10 January 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"14"}}