title: Acute and chronic effects of IL-22 on acetaminophen-induced liver injury.
abstract: Acetaminophen (APAP)-induced liver injury (AILI) accounts for half of the acute liver failure cases in the United States. A better understanding of the underlying mechanisms of AILI is necessary for the development of novel antidotes. We found that pretreatment with IL-22 protected mice from APAP-mediated hepatotoxicity. The protection was dependent on STAT3, as IL-22 failed to reduce APAP hepatotoxicity in liver-specific STAT3 knockout mice. In contrast to the acute exposure to IL-22, the endogenous chronic overexpression of IL-22 in IL-22 transgenic (TG) mice or IL-22 adenovirus treatment for 6 wk resulted in a markedly increased susceptibility to AILI. Furthermore, the hepatic expression levels of cytochrome 2E1 (Cyp2E1) and Cyp1A2 were much higher in IL-22TG mice. Ablation of Cyp2E1 but not hepatic STAT3 abolished AILI and protein-adduct formation in IL-22TG mice. Finally, hepatic expression of HNF-1α, a transcriptional factor that is known to control Cyp2E1 expression, was elevated in IL-22TG mice compared with wild-type mice. Upregulation of hepatic Cyp2E1 was only observed in mice with constitutive overexpression of IL-22 but not with short-term treatment with one dose of IL-22 or multiple doses of IL-22 for 2 wk. In conclusion, short-term acute IL-22 exposure protects mice against AILI through STAT3 activation; however, chronic constitutive overexpression of IL-22 exacerbates AILI by increasing Cyp2E1 and toxic reactive APAP metabolite production. These findings may not only enhance our understanding of the effects of chronic inflammation on AILI in patients with liver disease, but are also helpful to identify novel therapeutic targets for the treatment of AILI.
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors: Dechun
authors: D
authors: Feng
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors: Yan
authors: Y
authors: Wang
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors: Hua
authors: H
authors: Wang
authors: Medical Clinic, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim 68167, Germany;
authors: Honglei
authors: H
authors: Weng
authors: School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China; and.
authors: Xiaoni
authors: X
authors: Kong
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors: Brittany V
authors: BV
authors: Martin-Murphy
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors: Yongmei
authors: Y
authors: Li
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors: Ogyi
authors: O
authors: Park
authors: Medical Clinic, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim 68167, Germany;
authors: Steven
authors: S
authors: Dooley
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors: Cynthia
authors: C
authors: Ju
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; bgao@mail.nih.gov.
authors: Bin
authors: B
authors: Gao
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002908:Chronic Disease; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000276:immunology; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D019392:Cytochrome P-450 CYP2E1; D051538:Hepatocyte Nuclear Factor 1-alpha; D007378:Interleukins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C496488:Hnf1a protein, mouse; C494087:Stat3 protein, mouse