Background: Autophagy (self-digestion), is a cellular pathway crucial for differentiation, survival, and homeostasis. We have shown that exogenous IL-22 regulates liver IRI by activating STAT3 signaling. We hypothesize that IL-22 may promote parenchymal autophagy, hepatocellular survival/regeneration by activating STAT3–c-myc. Methods&Results: We used conditional IL-22Tg mice (B6; under the control of Albumin promoter) in which hepatocytes selectively overexpress IL-22. In a model of warm hepatic ischemia (90min), followed by reperfusion (6h), IL-22Tg mice were protected against liver IRI, evidenced by reduced sALT levels (611±241 U/L vs. 6055±2286 U/L in controls, p<0.001) and preserved hepatic architecture. We then assessed autophagy activity in IL-22Tg vs. WT livers subjected to IR insult. Interestingly, hepatic IL-22 overexpression enhanced local autophagy, evidenced by increased LC-3a and Beclin-1 gene induction. We then focused on c-myc, STAT3 downstream cell survival factor. Indeed, c-myc gene induction peaked at 6h of reperfusion, the time of maximal hepatocellular damage in vivo, and its frequency was enhanced in IL-22Tg liver IRI. This effect was accompanied by up-regulation of STAT3 phosphorylation, enhancement of autophagy and HGF (Hepatocyte Growth Factor)/c-Met signaling. Strikingly, IL-22-facilitated autophagy in vivo was abolished and the hepatocellular injury was restored after adjunctive treatment with STAT3 chemical inhibitor (S3I-201) or c-myc inhibitor (10058-F4). Consistently, IL-22-induced autophagy further prevented hydrogen peroxide (H₂O₂)-mediated hepatocyte necrosis in primary hepatocyte cultures in vitro. The cytoprotective effects of IL-22 on hepatocytes were confirmed by decreased cytoplasmic LDH release, increased conversion of LC3-I/LC3-II, and abundant visualized endogenous LC3 punctae. In contrast, addition of STAT3 or c-myc inhibitors reversed IL-22-induced hepatocellular autophagy/survival in vitro. Conclusion: This is the first study to provide evidence that IL-22 may: 1) promote hepatocellular autophagy in pathophysiology of liver IRI; 2) enhance STAT3–c-myc pathway; 3) exert cytoprotrotection via integrated IL-22-STAT3–c-myc signaling network in hepatocellular autophagy. These findings identify IL-22 as a novel regulator of hepatocyte survival in a therapeutic regimen against organ IRI in transplant recipients.

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