Most of the IL-22 transgenic mice died within the first few days after birth. In addition, Savan et al.19 developed transgenic mice in which IL-22R1 was expressed
on lymphocytes. These mice died of inflammation 6-8 weeks after birth and also showed high levels of circulating IL-22, thus demonstrating that aberrant expression of IL-22R1 was sufficient to drive IL-22 production by lymphocytes. In this study, we demonstrate that a high percentage of inflammatory cells in patients with chronic hepatitis B virus (HBV) find more or hepatitis C virus (HCV) expressed IL-22 and that the number of IL-22–positive cells correlates positively with the grade of liver inflammation and serum levels of aspartate aminotransferase, thus implicating IL-22–expressing lymphocytes as mediators of pathogenesis in these diseases. At present, there are no small animal models available with chronic viral hepatitis and liver inflammation that are associated with elevation of IL-22 in the liver. As mentioned above, transgenic mice with IL-22 overexpression in lymphoid cells died within the first few days after birth.18 Thus, in order to define the role of elevated
IL-22 in the pathogenesis of liver disease, we developed transgenic mice with overexpression of IL-22 in the liver under the control of the albumin promoter to imitate selleck products the situation in viral hepatitis patients with high levels of IL-22 in the liver. In contrast to EμLCK promoter–driven or the rat insulin II promoter–driven IL-22TG mice,18 liver-specific IL-22TG had no obvious adverse phenotypes and no overt inflammation, but were completely resistant to T cell hepatitis, had medchemexpress accelerated liver regeneration after partial hepatectomy, and showed increased sensitivity to diethylnitrosamine (DEN)-induced liver cancer. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ConA, concanavalin A; DEN, diethylnitrosamine; HBV, hepatitis B virus; HCV, hepatitis C virus; IL-22, interleukin-22; PCR, polymerase chain reaction; PHx, partial
hepatectomy; pSTAT, phosphorylated signal transducer and activator of transcription; SAA, serum amyloid A; STAT, signal transducer and activator of transcription; TG, transgenic; WT, wild-type. Most human cirrhotic liver samples were obtained from recipient livers after transplantation; some liver samples from patients with chronic HBV or HCV were obtained by way of biopsy (Supporting Information Table 1). Evaluation of severity of disease followed the Scheuer criterion. The degree of inflammatory infiltration was defined as grade (G), and the degree of fibrosis was defined as stage (S). Normal healthy liver samples were obtained from normal healthy donors for liver transplantation. The study protocol involved in human samples was approved by the local ethics committee, and all patients provided written informed consent.