{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:48:38Z","timestamp":1789645718331,"version":"4.0.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":942,"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":[[2013,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail<\/jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 <\/jats:bold>\n                                 <jats:bold>. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A\u2013induced tissue injury<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>, which was strongly associated with reduced liver cell apoptosis.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion:<\/jats:title>\n            <jats:p>\n                                 <jats:bold>The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10\/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26069","type":"journal-article","created":{"date-parts":[[2012,9,19]],"date-time":"2012-09-19T16:37:46Z","timestamp":1348072666000},"page":"797-805","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":58,"title":["Proapoptotic Effects of the Chemokine, CXCL 10 Are Mediated by the Noncognate Receptor TLR4 in Hepatocytes"],"prefix":"10.1097","volume":"57","author":[{"given":"Hacer","family":"Sahin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erawan","family":"Borkham-Kamphorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole T.","family":"do O","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"Berres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kaldenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Liedtke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad L.","family":"Streetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Maedler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann E.","family":"Wasmuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-38-20241201","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":"R2-38-20241201","doi-asserted-by":"crossref","first-page":"11651194","DOI":"10.1152\/physrev.00061.2009","article-title":"Hepatocyte death: a clear and present danger.","volume":"90","author":"Malhi","year":"2010","journal-title":"Physiol Rev"},{"key":"R3-38-20241201","doi-asserted-by":"crossref","first-page":"215225","DOI":"10.1055\/s-0030-1255351","article-title":"Chemokines in liver inflammation and fibrosis.","volume":"30","author":"Wasmuth","year":"2010","journal-title":"Semin Liver Dis"},{"key":"R4-38-20241201","doi-asserted-by":"crossref","first-page":"682690","DOI":"10.1038\/nrgastro.2010.168","article-title":"Functional role of chemokines in liver disease models.","volume":"7","author":"Sahin","year":"2010","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"R5-38-20241201","doi-asserted-by":"crossref","first-page":"62366243","DOI":"10.4049\/jimmunol.163.11.6236","article-title":"Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis Cinfected liver.","volume":"163","author":"Shields","year":"1999","journal-title":"J Immunol"},{"key":"R6-38-20241201","doi-asserted-by":"crossref","first-page":"15371549","DOI":"10.1084\/jem.20021897","article-title":"An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP10, Mig, and ITAC, and acts as functional receptor for platelet factor 4.","volume":"197","author":"Lasagni","year":"2003","journal-title":"J Exp Med"},{"key":"R8-38-20241201","doi-asserted-by":"crossref","first-page":"16101619","DOI":"10.1002\/hep.25545","article-title":"Chemokine Cxcl9 attenuates liver fibrosisassociated angiogenesis in mice.","volume":"55","author":"Sahin","year":"2012","journal-title":"HEPATOLOGY"},{"key":"R9-38-20241201","doi-asserted-by":"crossref","first-page":"424435","DOI":"10.1016\/j.jaut.2010.09.003","article-title":"CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation.","volume":"35","author":"Hintermann","year":"2010","journal-title":"J Autoimmun"},{"key":"R10-38-20241201","doi-asserted-by":"crossref","first-page":"13451353","DOI":"10.1002\/hep.23435","article-title":"CXC chemokine ligand 4 (Cxcl4) is a plateletderived mediator of experimental liver fibrosis.","volume":"51","author":"Zaldivar","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R11-38-20241201","doi-asserted-by":"crossref","first-page":"191197","DOI":"10.1007\/s00795-007-0371-x","article-title":"Neutralization of CXCL10 accelerates liver regeneration in carbon tetrachlorideinduced acute liver injury.","volume":"40","author":"Yoneyama","year":"2007","journal-title":"Med Mol Morphol"},{"key":"R12-38-20241201","doi-asserted-by":"crossref","first-page":"14401450","DOI":"10.1002\/hep.22500","article-title":"Intrahepatic levels of CXCR3associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.","volume":"48","author":"Zeremski","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R13-38-20241201","doi-asserted-by":"crossref","first-page":"596603","DOI":"10.1002\/hep.24098","article-title":"Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection.","volume":"53","author":"Berres","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R14-38-20241201","doi-asserted-by":"crossref","first-page":"256259","DOI":"10.4161\/isl.1.3.9110","article-title":"CXCL10a path to betacell death.","volume":"1","author":"Paroni","year":"2009","journal-title":"Islets"},{"key":"R15-38-20241201","doi-asserted-by":"crossref","first-page":"210223","DOI":"10.1111\/j.1365-2613.2009.00697.x","article-title":"Potential role of CXCL10 in the induction of cell injury and mitochondrial dysfunction.","volume":"91","author":"Singh","year":"2010","journal-title":"Int J Exp Pathol"},{"key":"R16-38-20241201","doi-asserted-by":"crossref","first-page":"62476258","DOI":"10.1128\/MCB.25.14.6247-6258.2005","article-title":"Gamma interferoninducible protein 10 induces HeLa cell apoptosis through a p53dependent pathway initiated by suppression of human papillomavirus type 18 E6 and E7 expression.","volume":"25","author":"Zhang","year":"2005","journal-title":"Mol Cell Biol"},{"key":"R17-38-20241201","doi-asserted-by":"crossref","first-page":"41294140","DOI":"10.1172\/JCI41732","article-title":"Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice.","volume":"120","author":"Berres","year":"2010","journal-title":"J Clin Invest"},{"key":"R18-38-20241201","doi-asserted-by":"crossref","first-page":"21762187","DOI":"10.1053\/j.gastro.2011.08.037","article-title":"Loss of caspase8 protects mice against inflammationrelated hepatocarcinogenesis but induces nonapoptotic liver injury.","volume":"141","author":"Liedtke","year":"2011","journal-title":"Gastroenterology"},{"key":"R19-38-20241201","doi-asserted-by":"crossref","first-page":"52845293","DOI":"10.4049\/jimmunol.1003750","article-title":"CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immunemediated hepatitis.","volume":"186","author":"Erhardt","year":"2011","journal-title":"J Immunol"},{"key":"R20-38-20241201","doi-asserted-by":"crossref","first-page":"17291738","DOI":"10.1053\/j.gastro.2008.07.065","article-title":"Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis.","volume":"135","author":"Taura","year":"2008","journal-title":"Gastroenterology"},{"key":"R21-38-20241201","first-page":"13421353","article-title":"Adenoviral CCN3NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis.","volume":"32","author":"BorkhamKamphorst","year":"2012","journal-title":"Liver Int"},{"key":"R22-38-20241201","doi-asserted-by":"crossref","first-page":"3867538685","DOI":"10.1074\/jbc.M306494200","article-title":"Caspaseactivated PAK2 is regulated by subcellular targeting and proteasomal degradation.","volume":"278","author":"Jakobi","year":"2003","journal-title":"J Biol Chem"},{"key":"R23-38-20241201","doi-asserted-by":"crossref","first-page":"720722","DOI":"10.1096\/fj.03-0771fje","article-title":"Differential requirement for cJun NH2terminal kinase in TNFalpha and Fasmediated apoptosis in hepatocytes.","volume":"18","author":"Schwabe","year":"2004","journal-title":"FASEB J"},{"key":"R24-38-20241201","doi-asserted-by":"crossref","first-page":"125139","DOI":"10.1016\/j.cmet.2009.01.003","article-title":"CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling.","volume":"9","author":"Schulthess","year":"2009","journal-title":"Cell Metab"},{"key":"R25-38-20241201","doi-asserted-by":"crossref","first-page":"612620","DOI":"10.1016\/j.jhep.2010.07.042","article-title":"HIV infection increases HCVinduced hepatocyte apoptosis.","volume":"54","author":"Jang","year":"2011","journal-title":"J Hepatol"},{"key":"R26-38-20241201","doi-asserted-by":"crossref","first-page":"196203","DOI":"10.1172\/JCI115836","article-title":"A T celldependent experimental liver injury in mice inducible by concanavalin A.","volume":"90","author":"Tiegs","year":"1992","journal-title":"J Clin Invest"},{"key":"R27-38-20241201","first-page":"70777083","article-title":"IFNgammainducible protein10 (CXCL10) is hepatoprotective during acute liver injury through the induction of CXCR2 on hepatocytes.","volume":"167","author":"BoneLarson","year":"2001","journal-title":"J Immunol"},{"key":"R28-38-20241201","doi-asserted-by":"crossref","first-page":"11651175","DOI":"10.1111\/j.1365-2826.2008.01769.x","article-title":"Akt induces apoptosis in neuroblastoma cells expressing a C98X vasopressin mutant following autophagy suppression.","volume":"20","author":"Castino","year":"2008","journal-title":"J Neuroendocrinol"},{"key":"R29-38-20241201","doi-asserted-by":"crossref","first-page":"67856793","DOI":"10.4049\/jimmunol.176.11.6785","article-title":"Phosphatidylinositol 3kinaseAkt positively regulates Fas (CD95)mediated apoptosis in epidermal Cl41 cells.","volume":"176","author":"Lu","year":"2006","journal-title":"J Immunol"},{"key":"R30-38-20241201","doi-asserted-by":"crossref","first-page":"91069109","DOI":"10.1074\/jbc.275.13.9106","article-title":"The Akt protooncogene links Ras to Pak and cell survival signals.","volume":"275","author":"Tang","year":"2000","journal-title":"J Biol Chem"},{"key":"R31-38-20241201","doi-asserted-by":"crossref","first-page":"711","DOI":"10.4049\/jimmunol.160.1.7","article-title":"p21activated kinase (PAK) is required for Fasinduced JNK activation in Jurkat cells.","volume":"160","author":"Rudel","year":"1998","journal-title":"J Immunol"},{"key":"R32-38-20241201","doi-asserted-by":"crossref","first-page":"306317","DOI":"10.1007\/s00335-011-9326-6","article-title":"Functional PAK2 knockout and replacement with a caspase cleavagedeficient mutant in mice reveals differential requirements of fulllength PAK2 and caspaseactivated PAK2p34.","volume":"22","author":"Marlin","year":"2011","journal-title":"Mamm Genome"},{"key":"R33-38-20241201","doi-asserted-by":"crossref","first-page":"e12700","DOI":"10.1371\/journal.pone.0012700","article-title":"CXCL10 can inhibit endothelial cell proliferation independently of CXCR3.","volume":"5","author":"Campanella","year":"2010","journal-title":"PLoS One"},{"key":"R34-38-20241201","doi-asserted-by":"crossref","first-page":"13241332","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGFbeta signaling and hepatic fibrosis.","volume":"13","author":"Seki","year":"2007","journal-title":"Nat Med"},{"key":"R35-38-20241201","doi-asserted-by":"crossref","first-page":"10581067","DOI":"10.1136\/gutjnl-2011-300269","article-title":"Tolllike receptor4 mediates obesityinduced nonalcoholic steatohepatitis through activation of Xbox binding protein1 in mice.","volume":"61","author":"Ye","year":"2012","journal-title":"Gut"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26069","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201302000-00038","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T14:05:51Z","timestamp":1733061951000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201302000-00038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26069","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2013,2]]}}}