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

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.