In vivoconsequences of liver-specific interleukin-22... : Hepatology (original) (raw)

Liver Biology/Pathobiology

In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression

Park, Ogyi1; Wang, Hua1; Weng, Honglei2; Feigenbaum, Lionel3; Li, Hai4; Yin, Shi1; Ki, Sung Hwan1; Yoo, Seong Ho5; Dooley, Steven2; Wang, Fu-Sheng6; Young, Howard A.7; Gao, Bin1

1_Laboratory of Liver Diseases and the_

5_Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD; the_

2_Molecular Hepatology–Alcohol Associated Diseases, II, Medical Clinic, Medical Faculty Mannheim at Heidelberg University, Mannheim, Germany; the_

3_Laboratory of Animal Science Program, Center for Cancer Research and the_

7_Laboratory of Experimental Immunology, Cancer and Inflammation Program, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD; the_

4_Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University, Shanghai, China; and the_

6_Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China_

Current address for S.H.K.: Laboratory of Toxicology, College of Pharmacy, Chosun University, South Korea

M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892 E-mail:[email protected]

Potential conflict of interest: Nothing to report.

*These authors contributed equally to this work. Supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism (B.G.) and the National Cancer Institute (H.A.Y.), and by the German Federal Ministry for Education and Research (BMBF) grants “Virtual Liver” and “Cell Therapy” (H.W., S.D.).

fax: 301–480–0257

Abstract

Interleukin-22 (IL-22), which acts as either a proinflammatory or anti-inflammatory cytokine in various disease models, is markedly up-regulated in chronic liver diseases, including hepatitis B and C. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 up-regulation in the pathogenesis of liver diseases, liver-specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4,000 to 7,000 pg/mL, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation (except for slightly thicker epidermis and minor inflammation of the skin) compared with wild-type mice. Interestingly, IL-22TG mice were completely resistant to concanavalin A–induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of antioxidant, mitogenic, acute phase genes were up-regulated in the livers of IL-22TG mice compared with those from wild-type mice. Conclusion: These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation. (HEPATOLOGY 2011;)