{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:58:07Z","timestamp":1790449087074,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T00:00:00Z","timestamp":1656115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Medical Research Council (NMRC)","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}]},{"name":"National Medical Research Council (NMRC)","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}]},{"name":"National Medical Research Council (NMRC)","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}]},{"DOI":"10.13039\/501100001349","name":"Singapore STaR","doi-asserted-by":"publisher","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"Singapore STaR","doi-asserted-by":"publisher","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"Singapore STaR","doi-asserted-by":"publisher","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC-LMS (UK)","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}]},{"name":"MRC-LMS (UK)","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}]},{"name":"MRC-LMS (UK)","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}]},{"name":"Goh Foundation","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}]},{"name":"Goh Foundation","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}]},{"name":"Goh Foundation","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}]},{"name":"Tanoto Foundation","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}]},{"name":"Tanoto Foundation","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}]},{"name":"Tanoto Foundation","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}]},{"name":"Khoo Foundation","award":["NMRC\/STaR\/0029\/2017"],"award-info":[{"award-number":["NMRC\/STaR\/0029\/2017"]}]},{"name":"Khoo Foundation","award":["MOH-CIRG18nov-0002"],"award-info":[{"award-number":["MOH-CIRG18nov-0002"]}]},{"name":"Khoo Foundation","award":["NMRC\/OFYIRG\/0053\/2017"],"award-info":[{"award-number":["NMRC\/OFYIRG\/0053\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11\/IL11RA\/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT\/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK\/JNK\/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1\u03b2, and Tnf\u03b1 expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.<\/jats:p>","DOI":"10.3390\/ijms23137089","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"7089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury"],"prefix":"10.3390","volume":"23","author":[{"given":"Jinrui","family":"Dong","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0311-943X","authenticated-orcid":false,"given":"Wei-Wen","family":"Lim","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5592-7362","authenticated-orcid":false,"given":"Shamini G.","family":"Shekeran","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Tan","sequence":"additional","affiliation":[{"name":"National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sze Yun","family":"Lim","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-4195","authenticated-orcid":false,"given":"Joyce Wei Ting","family":"Goh","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin L.","family":"George","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Schafer","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Cook","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore"},{"name":"MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9404-7608","authenticated-orcid":false,"given":"Anissa A.","family":"Widjaja","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liongue, C., and Ward, A.C. (2007). Evolution of Class I Cytokine Receptors. BMC Evol. Biol., 7.","DOI":"10.1186\/1471-2148-7-120"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature24676","article-title":"IL-11 Is a Crucial Determinant of Cardiovascular Fibrosis","volume":"552","author":"Schafer","year":"2017","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1053\/j.gastro.2019.05.002","article-title":"Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis","volume":"157","author":"Widjaja","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1080\/21645515.2020.1761203","article-title":"Different Roles of Interleukin 6 and Interleukin 11 in the Liver: Implications for Therapy","volume":"16","author":"Widjaja","year":"2020","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/978-1-62703-308-4_4","article-title":"The Regenerative Activity of Interleukin-6","volume":"982","author":"Galun","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11281","DOI":"10.1074\/jbc.M208470200","article-title":"Interleukin-6\/glycoprotein 130-Dependent Pathways Are Protective during Liver Regeneration","volume":"278","author":"Wuestefeld","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S0016-5085(03)00901-6","article-title":"Lack of gp130 Expression in Hepatocytes Promotes Liver Injury","volume":"125","author":"Streetz","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9886","DOI":"10.1074\/jbc.M705483200","article-title":"Molecular Dissection of gp130-Dependent Pathways in Hepatocytes during Liver Regeneration","volume":"283","author":"Dierssen","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1006\/mthe.2001.0313","article-title":"Hyper-IL-6 Gene Therapy Reverses Fulminant Hepatic Failure","volume":"3","author":"Hecht","year":"2001","journal-title":"Mol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1096\/fj.99-0913com","article-title":"Liver Regeneration Induced by a Designer Human IL-6\/sIL-6R Fusion Protein Reverses Severe Hepatocellular Injury","volume":"14","author":"Galun","year":"2000","journal-title":"FASEB J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e68843","DOI":"10.7554\/eLife.68843","article-title":"The pro-Regenerative Effects of HyperIL6 in Drug Induced Liver Injury Are Unexpectedly due to Competitive Inhibition of IL11 Signaling","volume":"10","author":"Dong","year":"2021","journal-title":"eLife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1681\/ASN.2021040577","article-title":"A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome","volume":"33","author":"Widjaja","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-med-041818-011649","article-title":"Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation","volume":"71","author":"Cook","year":"2020","journal-title":"Annu. Rev. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1080\/019262301317052521","article-title":"Protective Effect of rhIL-11 in a Murine Model of Acetaminophen-Induced Hepatotoxicity","volume":"29","author":"Trepicchio","year":"2001","journal-title":"Toxicol. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/hep.510300616","article-title":"Interleukin-11 Reduces T-Cell-Dependent Experimental Liver Injury in Mice","volume":"30","author":"Bozza","year":"1999","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"ra5","DOI":"10.1126\/scisignal.2002056","article-title":"Interleukin-11 Links Oxidative Stress and Compensatory Proliferation","volume":"5","author":"Nishina","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1074\/jbc.M116.744755","article-title":"Critical Contribution of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) to Electrophile-Induced Interleukin-11 Production","volume":"292","author":"Nishina","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaba8146","DOI":"10.1126\/scitranslmed.aba8146","article-title":"Redefining IL11 as a Regeneration-Limiting Hepatotoxin and Therapeutic Target in Acetaminophen-Induced Liver Injury","volume":"13","author":"Widjaja","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41467-020-20303-z","article-title":"Hepatocyte-Specific IL11 Cis-Signaling Drives Lipotoxicity and Underlies the Transition from NAFLD to NASH","volume":"12","author":"Dong","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Effenberger, M., Widjaja, A.A., Grabherr, F., Schaefer, B., Grander, C., Mayr, L., Schwaerzler, J., Enrich, B., Moser, P., and Fink, J. (2022). Interleukin-11 Drives Human and Mouse Alcohol-Related Liver Disease. Gut.","DOI":"10.1101\/2021.08.24.456749"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1073\/pnas.93.1.407","article-title":"Targeted Disruption of gp130, a Common Signal Transducer for the Interleukin 6 Family of Cytokines, Leads to Myocardial and Hematological Disorders","volume":"93","author":"Yoshida","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<151::AID-GENE17>3.0.CO;2-E","article-title":"Hepatocyte-Specific Expression of Cre Recombinase","volume":"26","author":"Kellendonk","year":"2000","journal-title":"Genesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4610","DOI":"10.1096\/fj.201801976R","article-title":"Hepatocyte and Stellate Cell Deletion of Liver Fatty Acid Binding Protein Reveals Distinct Roles in Fibrogenic Injury","volume":"33","author":"Newberry","year":"2019","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"G412","DOI":"10.1152\/ajpgi.00590.2007","article-title":"Optimized Adeno-Associated Virus 8 Produces Hepatocyte-Specific Cre-Mediated Recombination without Toxicity or Affecting Liver Regeneration","volume":"295","author":"Ho","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1016\/j.lfs.2005.07.003","article-title":"Role of Caspases in Acetaminophen-Induced Liver Injury","volume":"78","author":"Jaeschke","year":"2006","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1006\/taap.1999.8635","article-title":"Inhibition of Fas Receptor (CD95)-Induced Hepatic Caspase Activation and Apoptosis by Acetaminophen in Mice","volume":"156","author":"Lawson","year":"1999","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.biopha.2017.12.076","article-title":"Simvastatin Protects against Acetaminophen-Induced Liver Injury in Mice","volume":"98","author":"Liang","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liao, C.-C., Day, Y.-J., Lee, H.-C., Liou, J.-T., Chou, A.-H., and Liu, F.-C. (2016). Baicalin Attenuates IL-17-Mediated Acetaminophen-Induced Liver Injury in a Mouse Model. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166856"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1126\/science.274.5291.1379","article-title":"Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice","volume":"274","author":"Cressman","year":"1996","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/hep.23322","article-title":"Lack of Interleukin-6\/glycoprotein 130\/signal Transducers and Activators of Transcription-3 Signaling in Hepatocytes Predisposes to Liver Steatosis and Injury in Mice","volume":"51","author":"Kroy","year":"2010","journal-title":"Hepatology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.2353\/ajpath.2010.090469","article-title":"Lack of Glycoprotein 130\/signal Transducer and Activator of Transcription 3-Mediated Signaling in Hepatocytes Enhances Chronic Liver Injury and Fibrosis Progression in a Model of Sclerosing Cholangitis","volume":"176","author":"Plum","year":"2010","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:38:31Z","timestamp":1760139511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,25]]},"references-count":31,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137089"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137089","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,25]]}}}