دورية أكاديمية
Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.
| العنوان: | Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. |
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| المؤلفون: | Widjaja AA; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore. stuart.cook@duke-nus.edu.sg anissa.widjaja@duke-nus.edu.sg., Dong J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Adami E; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Viswanathan S; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Ng B; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore., Pakkiri LS; Cardiac Department, National University Hospital, Singapore 119074, Singapore., Chothani SP; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Singh BK; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Lim WW; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore., Zhou J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Shekeran SG; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Tan J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore., Lim SY; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore., Goh J; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Wang M; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Holgate R; Abzena, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK., Hearn A; Abzena, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK., Felkin LE; National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK., Yen PM; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore., Dear JW; Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK., Drum CL; Cardiovascular Research Institute, National University Health System, Singapore 119228, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore., Schafer S; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore., Cook SA; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore. stuart.cook@duke-nus.edu.sg anissa.widjaja@duke-nus.edu.sg.; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore.; MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK. |
| المصدر: | Science translational medicine [Sci Transl Med] 2021 Jun 09; Vol. 13 (597). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Chemical and Drug Induced Liver Injury*/drug therapy , Chemical and Drug Induced Liver Injury, Chronic*, Acetaminophen/toxicity ; Animals ; Hepatocytes ; Interleukin-11 ; Interleukin-11 Receptor alpha Subunit ; Liver ; Mice ; Mice, Inbred C57BL |
| مستخلص: | Acetaminophen ( N -acetyl- p -aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 ( Il11ra1 ) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.) |
| التعليقات: | Comment in: Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):523. (PMID: 34183810) |
| معلومات مُعتمدة: | MC_U120085815 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (Il11ra1 protein, mouse) 0 (Interleukin-11) 0 (Interleukin-11 Receptor alpha Subunit) 362O9ITL9D (Acetaminophen) |
| تواريخ الأحداث: | Date Created: 20210610 Date Completed: 20210712 Latest Revision: 20220223 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1126/scitranslmed.aba8146 |
| PMID: | 34108253 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.aba8146 |