{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:08:49Z","timestamp":1790888929816,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1704,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>The immunopathogenic process from hepatitis B virus (HBV) infection to liver fibrosis is incompletely understood because it lacks an animal model. In this study we observed the development of liver fibrosis in HBV transgenic (HBV-tg) mice and found the roles of natural killer T (NKT) cells in HBV-related liver fibrosis. We found liver fibrosis spontaneously developed in HBV-tg mice with the elevated transcription of col1a1, matrix metalloproteinase (MMP)2, and tissue inhibitor of metalloproteinase (TIMP)1. Mice were then injected with repetitive hepatotoxin carbon tetrachloride (CCl4) to induce prominent liver fibrosis. After chronic CCl4 treatment, the serum alanine aminotransferase (ALT) was higher, the liver regenerative nodules became more and bigger, and the fibrosis area was remarkably increased in HBV-tg mice than in C57BL\/6 mice. Moreover, the increase in col1a1 and MMP2 transcription was greater, with a sustaining high level of TIMP1 and a greater activation of hepatic stellate cells (HSCs) in the livers of CCl4-treated HBV-tg mice. Our data also showed that there were more liver mononuclear cells (MNCs) in HBV-tg mice after CCl4 injection, and Rag1\u2212\/\u2212 mice adoptive transferred lymphocytes from HBV-tg mice displayed increased collagen deposition. Further study demonstrated the number of liver NKT cells increased after CCl4 treatment and NKT cells were overactivated in HBV-tg mice in the long term. It was further confirmed that NKT cells were critical for HSCs activation by depletion of NKT cells of HBV-tg mice and adoptive transfer of purified NKT cells from HBV-tg mice into recipient Rag1\u2212\/\u2212 mice. The inflammatory cytokines IL-4 and IL-13 produced by NKT cells played a pivotal role in HSCs activation in an<\/jats:bold>\n                      <jats:bold>in vitro<\/jats:bold>\n                      <jats:bold>coculture experiment.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      <jats:bold>These data suggest that NKT cells from HBV-tg mice induce the HSC activation in liver fibrogenesis. (Hepatology 2011;.)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23983","type":"journal-article","created":{"date-parts":[[2010,9,14]],"date-time":"2010-09-14T09:06:02Z","timestamp":1284455162000},"page":"219-229","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":89,"title":["Accelerated liver fibrosis in hepatitis B virus transgenic mice: Involvement of natural killer T cells"],"prefix":"10.1097","volume":"53","author":[{"given":"Zixue","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-24-20250207","doi-asserted-by":"crossref","first-page":"209218","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis.","volume":"115","author":"Bataller","year":"2005","journal-title":"J Clin Invest"},{"key":"R2-24-20250207","doi-asserted-by":"crossref","first-page":"16551669","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis.","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"R3-24-20250207","doi-asserted-by":"crossref","first-page":"7699","DOI":"10.1111\/j.1582-4934.2006.tb00292.x","article-title":"Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGFbeta as major players and therapeutic targets.","volume":"10","author":"Gressner","year":"2006","journal-title":"J Cell Mol Med"},{"key":"R4-24-20250207","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00795-003-0230-3","article-title":"Structure and function of hepatic stellate cells.","volume":"37","author":"Senoo","year":"2004","journal-title":"Med Electron Microsc"},{"key":"R5-24-20250207","doi-asserted-by":"crossref","first-page":"242249","DOI":"10.1002\/hep.21459","article-title":"Hepatic fibrosis 2006: report of the Third AASLD Single Topic Conference.","volume":"45","author":"Friedman","year":"2007","journal-title":"HEPATOLOGY"},{"key":"R6-24-20250207","first-page":"434439","article-title":"Liver fibrosis: searching for cell model answers.","volume":"27","author":"GutierrezRuiz","year":"2007","journal-title":"Liver Int"},{"key":"R7-24-20250207","doi-asserted-by":"crossref","first-page":"98105","DOI":"10.1038\/ncpgasthep0055","article-title":"Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications.","volume":"1","author":"Friedman","year":"2004","journal-title":"Nat Clin Pract Gastroenterol Hepatol"},{"key":"R8-24-20250207","doi-asserted-by":"crossref","first-page":"521526","DOI":"10.1002\/hep.21347","article-title":"Global challenges in liver disease.","volume":"44","author":"Williams","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R9-24-20250207","doi-asserted-by":"crossref","first-page":"529538","DOI":"10.1016\/j.jhep.2006.05.013","article-title":"The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.","volume":"45","author":"Perz","year":"2006","journal-title":"J Hepatol"},{"key":"R10-24-20250207","first-page":"644651","article-title":"Liver fibrosis and chronic viral hepatitis.","volume":"38","author":"GutierrezReyes","year":"2007","journal-title":"Arch Med Res"},{"key":"R11-24-20250207","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.1016\/j.clinbiochem.2005.10.004","article-title":"Polymorphisms of glutathione Stransferase M1, T1, and P1 in patients with HBVrelated liver cirrhosis, chronic hepatitis, and normal carriers.","volume":"39","author":"Mohammadzadeh Ghobadloo","year":"2006","journal-title":"Clin Biochem"},{"key":"R12-24-20250207","doi-asserted-by":"crossref","first-page":"14881491","DOI":"10.1111\/j.1440-1746.2006.04527.x","article-title":"Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B.","volume":"21","author":"Xiao","year":"2006","journal-title":"J Gastroenterol Hepatol"},{"key":"R13-24-20250207","doi-asserted-by":"crossref","first-page":"564570","DOI":"10.1111\/j.1478-3231.2005.01041.x","article-title":"Basal corepromoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigennegative chronic hepatitis B.","volume":"25","author":"Lin","year":"2005","journal-title":"Liver Int"},{"key":"R14-24-20250207","first-page":"18721883","article-title":"The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells.","volume":"47","author":"MartinVilchez","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R15-24-20250207","doi-asserted-by":"crossref","first-page":"652662.e653.e653","DOI":"10.1053\/j.gastro.2008.10.048","article-title":"Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinasetype plasminogen activator mouse with human hepatocytes.","volume":"136","author":"Sugiyama","year":"2009","journal-title":"Gastroenterology"},{"key":"R16-24-20250207","doi-asserted-by":"crossref","first-page":"870882","DOI":"10.1053\/j.gastro.2004.04.062","article-title":"Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin10 from hepatocytes.","volume":"127","author":"Safadi","year":"2004","journal-title":"Gastroenterology"},{"key":"R17-24-20250207","doi-asserted-by":"crossref","first-page":"30723082","DOI":"10.1172\/JCI24798","article-title":"Attenuated liver fibrosis in the absence of B cells.","volume":"115","author":"Novobrantseva","year":"2005","journal-title":"J Clin Invest"},{"key":"R18-24-20250207","doi-asserted-by":"crossref","first-page":"G200207","DOI":"10.1152\/ajpgi.2001.281.1.G200","article-title":"Attenuation of CCl(4)induced hepatic fibrosis by GdCl(3) treatment or dietary glycine.","volume":"281","author":"Rivera","year":"2001","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R19-24-20250207","doi-asserted-by":"crossref","first-page":"14871501","DOI":"10.1002\/hep.21427","article-title":"Oxidativestress and IL6 mediate the fibrogenic effects of corrected Kupffer cells on stellate cells.","volume":"44","author":"Nieto","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R20-24-20250207","doi-asserted-by":"crossref","first-page":"435452","DOI":"10.1053\/j.gastro.2005.10.055","article-title":"Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2Ddependent and tumor necrosis factorrelated apoptosisinducing liganddependent manners.","volume":"130","author":"Radaeva","year":"2006","journal-title":"Gastroenterology"},{"key":"R21-24-20250207","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.1016\/j.jhep.2005.12.025","article-title":"Antifibrotic activity of NK cells in experimental liver injury through killing of activated HSC.","volume":"45","author":"Melhem","year":"2006","journal-title":"J Hepatol"},{"key":"R22-24-20250207","doi-asserted-by":"crossref","first-page":"16831694","DOI":"10.1002\/hep.22813","article-title":"Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.","volume":"49","author":"Park","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R23-24-20250207","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1038\/nri2451","article-title":"Harnessing invariant NKT cells in vaccination strategies.","volume":"9","author":"Cerundolo","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"R24-24-20250207","doi-asserted-by":"crossref","first-page":"583594","DOI":"10.1038\/nri1412","article-title":"Fibrotic disease and the T(H)1T(H)2 paradigm.","volume":"4","author":"Wynn","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"R25-24-20250207","doi-asserted-by":"crossref","first-page":"10211029","DOI":"10.1093\/intimm\/dxm069","article-title":"Amelioration of hepatic fibrosis via betaglucosylceramidemediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution.","volume":"19","author":"Safadi","year":"2007","journal-title":"Int Immunol"},{"key":"R26-24-20250207","doi-asserted-by":"crossref","first-page":"14171425","DOI":"10.4049\/jimmunol.173.2.1417","article-title":"Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis.","volume":"173","author":"de Lalla","year":"2004","journal-title":"J Immunol"},{"key":"R27-24-20250207","doi-asserted-by":"crossref","first-page":"11571160","DOI":"10.1126\/science.3865369","article-title":"A transgenic mouse model of the chronic hepatitis B surface antigen carrier state.","volume":"230","author":"Chisari","year":"1985","journal-title":"Science"},{"key":"R28-24-20250207","doi-asserted-by":"crossref","first-page":"940949","DOI":"10.1002\/hep.22725","article-title":"NKG2Dretinoic acid early inducible1 recognition between natural killer cells and Kupffer cells in a novel murine natural killer celldependent fulminant hepatitis.","volume":"49","author":"Hou","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R29-24-20250207","doi-asserted-by":"crossref","first-page":"117129","DOI":"10.1016\/j.immuni.2006.11.011","article-title":"Ito cells are liverresident antigenpresenting cells for activating T cell responses.","volume":"26","author":"Winau","year":"2007","journal-title":"Immunity"},{"key":"R30-24-20250207","doi-asserted-by":"crossref","first-page":"13761384","DOI":"10.1053\/j.gastro.2008.02.075","article-title":"Virologic and histologic features of chronic hepatitis B virusinfected asymptomatic patients with persistently normal ALT.","volume":"134","author":"Kumar","year":"2008","journal-title":"Gastroenterology"},{"key":"R31-24-20250207","first-page":"237250","article-title":"Modeling liver fibrosis in rodents.","volume":"117","author":"Constandinou","year":"2005","journal-title":"Methods Mol Med"},{"key":"R32-24-20250207","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1055\/s-2008-1040457","article-title":"Experimental models of hepatic fibrosis: a review.","volume":"10","author":"Tsukamoto","year":"1990","journal-title":"Semin Liver Dis"},{"key":"R33-24-20250207","doi-asserted-by":"crossref","first-page":"539548","DOI":"10.1172\/JCI30542","article-title":"Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ.","volume":"117","author":"Iredale","year":"2007","journal-title":"J Clin Invest"},{"key":"R34-24-20250207","doi-asserted-by":"crossref","first-page":"419428","DOI":"10.1016\/j.jhep.2006.04.010","article-title":"Liver fibrosis induced by hepatic overexpression of PDGFB in transgenic mice.","volume":"45","author":"Czochra","year":"2006","journal-title":"J Hepatol"},{"key":"R35-24-20250207","doi-asserted-by":"crossref","first-page":"1239812402","DOI":"10.1073\/pnas.92.26.12398","article-title":"Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyteactivated hepatocytes.","volume":"92","author":"Tsui","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R36-24-20250207","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1016\/S1074-7613(00)80295-2","article-title":"Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.","volume":"4","author":"Guidotti","year":"1996","journal-title":"Immunity"},{"key":"R37-24-20250207","doi-asserted-by":"crossref","first-page":"388391","DOI":"10.1016\/S1369-5274(99)80068-X","article-title":"Cytokineinduced viral purgingrole in viral pathogenesis.","volume":"2","author":"Guidotti","year":"1999","journal-title":"Curr Opin Microbiol"},{"key":"R38-24-20250207","doi-asserted-by":"crossref","first-page":"706715","DOI":"10.1002\/hep.21872","article-title":"Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2Dligand interaction and natural killer cells.","volume":"46","author":"Chen","year":"2007","journal-title":"HEPATOLOGY"},{"key":"R39-24-20250207","doi-asserted-by":"crossref","first-page":"1818718192","DOI":"10.1073\/pnas.0708968104","article-title":"Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus.","volume":"104","author":"Vilarinho","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R40-24-20250207","doi-asserted-by":"crossref","first-page":"691694","DOI":"10.1038\/372691a0","article-title":"Recognition of a lipid antigen by CD1restricted alpha beta T cells.","volume":"372","author":"Beckman","year":"1994","journal-title":"Nature"},{"key":"R41-24-20250207","doi-asserted-by":"crossref","first-page":"227230","DOI":"10.1126\/science.7542404","article-title":"CD1restricted T cell recognition of microbial lipoglycan antigens.","volume":"269","author":"Sieling","year":"1995","journal-title":"Science"},{"key":"R42-24-20250207","doi-asserted-by":"crossref","first-page":"359393","DOI":"10.1146\/annurev.immunol.16.1.359","article-title":"NK cell receptors.","volume":"16","author":"Lanier","year":"1998","journal-title":"Annu Rev Immunol"},{"key":"R43-24-20250207","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.clim.2008.08.008","article-title":"NK and NKT cells in liver injury and fibrosis.","volume":"130","author":"Notas","year":"2009","journal-title":"Clin Immunol"},{"key":"R44-24-20250207","doi-asserted-by":"crossref","first-page":"231237","DOI":"10.1038\/nri1309","article-title":"NKT cells: whats in a name?","volume":"4","author":"Godfrey","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"R45-24-20250207","doi-asserted-by":"crossref","first-page":"531534","DOI":"10.1038\/35097097","article-title":"A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells.","volume":"413","author":"Miyamoto","year":"2001","journal-title":"Nature"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.23983","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201101000-00024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T11:34:19Z","timestamp":1738928059000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201101000-00024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.23983","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2011,1]]}}}