| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Ju, Cynthia Li, Yongmei Weng, Honglei Dooley, Steven Martin-Murphy, Brittany V. Park, Ogyi Gao, Bin Feng, Dechun Kong, Xiaoni Wang, Hua Wang, Yan |
| Description |
Author Affiliation: Feng D ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892); Wang Y ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892); Wang H ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892); Weng H ( Medical Clinic, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim 68167, Germany); Kong X ( School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China); Martin-Murphy BV ( Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.); Li Y ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892); Park O ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892); Dooley S ( Medical Clinic, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim 68167, Germany); Ju C ( Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.); Gao B ( Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892) |
| 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-1 , 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. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1400588 |
| Journal |
The Journal of Immunology |
| Issue Number |
5 |
| Volume Number |
193 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2014-09-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Acetaminophen Adverse Effects Analgesics, Non-narcotic Interleukins Immunology Pharmacology Acute Disease Animals Drug-induced Liver Injury Drug Therapy Genetics Pathology Chronic Disease Cytochrome P-450 Cyp2e1 Gene Expression Regulation, Enzymologic Drug Effects Hepatocyte Nuclear Factor 1-alpha Mice Mice, Knockout Stat3 Transcription Factor Research Support, N.i.h., Intramural Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
