Finally, expression of IL-22R1 and IL-10R2 in the liver was comparable in WT and IL-22TG mice as demonstrated by reverse-transcription polymerase chain reaction (PCR) and real-time PCR (Supporting Information Fig. 2b). Next we compared the liver injury in WT and IL-22TG mice in a model of ConA-induced T cell hepatitis. As illustrated in Fig. 3A,B, IL-22TG mice were completely protected from the liver injury induced by ConA injection. Whereas WT and IL-22TG mice had comparable

levels of multiple cytokines and chemokines, including tumor necrosis factor α, IL-10, monocyte chemoattractant protein 1, and interferon-γ, serum levels of IL-6 were higher in WT mice than in IL-22TG mice (Fig. 2C). This increase in IL-6 may be due to massive liver necrosis observed find more in WT mice after ConA injection, because necrotic hepatocytes are known to stimulate Kupffer cells to produce IL-6.21 To further understand the mechanisms underlying the resistance of IL-22TG mice to XL765 chemical structure ConA-induced liver injury, we examined hepatic STAT3 and STAT1 activation, because these transcription factors play important roles in protecting against and promoting ConA-induced liver injury, respectively.22 As illustrated in Fig. 3D, ConA injection induced activation of both STAT3 and STAT1 in WT mice. In contrast,

IL-22TG mice had higher basal levels of pSTAT3, and activation of STAT3 was slightly enhanced whereas STAT1 activation was lower in IL-22TG mice compared with WT mice. Liver regeneration induced by partial hepatectomy (PHx) was also examined in IL-22TG mice. As illustrated in Fig. 4A, the liver/body weight ratio was similar before PHx (0) but was significantly higher in IL-22TG mice than in WT mice 32 hours, 48 hours, and 72 hours post-PHx, and returned to the same levels 96 hours after PHx in both groups. BrdU+ incorporation experiments demonstrated that IL-22TG mice had an accelerated peak of hepatocyte proliferation at 32 hours post-PHx, and

this peak is significantly higher when compared with WT mice. In addition, the number of BrdU+ hepatocytes was higher at 28 hours but lower at 48 hours post-PHx in IL-22TG mice versus WT mice, respectively, and was comparable 72 上海皓元 hours and 96 hours after surgery in both groups (Fig. 4B,C). These findings indicate that IL-22TG mice have accelerated liver regeneration after PHx. In order to define the underlying mechanism for this enhanced liver regeneration in IL-22TG mice, western blot analyses for STAT3 and STAT1 activation were performed. Figure 4D shows that STAT3 but not STAT1 activation was detected after PHx and that such activation was comparable between WT and IL-22TG mice. However, IL-22TG mice had higher basal levels of pSTAT3 than WT mice. In addition, expression of cyclin D1 was higher in IL-22TG mice than in WT mice prior to treatment and at early time points after PHx (Fig. 4D).