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Interleukin-22 (IL-22) has been proven to exhibit a protective role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to explore the change of IL-22 and IL-22 receptor 1 (IL-22R1) axis in HIRI and its role in mitochondrial apoptosis associated with STAT3 activation. I/R mice were examined for the expression of IL-22, IL-22R1 and IL-22BP. The roles of IL-22 in hepatic histopathology and oxidative stress injuries (ALT, MDA and SOD) were determined. Oxidative stress damages of AML-12 cells were induced by H 2 O 2 , and were indicated by apoptosis, Ca2+ concentration, and mitochondrial function. The effects of IL-22 on p-STAT3Try705 were analyzed. We found that the expression of IL-22, IL-22R1, and IL-22BP was elevated 24 h after I/R induction, while decreased 48 h after I/R induction. Furthermore, we also discovered that IL-22 rescued the morphological damages and dysfunction of hepatocytes induced by H 2 O 2 , which were antagonized by IL-22BP, an endogenous antagonist of IL-22. Additionally, increased levels of Ca2+ concentration, MDA, ROS, apoptosis and mitochondrial dysfunction were noticed in H 2 O 2 -treated hepatocytes. However, IL-22 ameliorated the effects of I/R or H 2 O 2. The protective effects of IL-22 were reversed by AG490, a specific antagonist of STAT3. In conclusion, our results indicated that IL-22 inhibited I/R-induced oxidative stress injury, Ca2+ overload, and mitochondrial apoptosis via STAT3 activation. • Exogenous IL-22 improves the morphology and function of hepatocytes. • IL-22BP, an antagonist of IL-22, antagonizes the hepatoprotective effects of IL-22. • IL-22 attenuates mitochondrial dysfunction and DNA damage in hepatocytes. • The effects of IL-22 are linked to the activation of JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-22 (IL-22) is an IL-10 family cytokine produced by T cells and innate lymphoid cells. The IL-22 signaling pathway orchestrates mucosal immune defense and tissue regeneration through pleiotropic effects including pro-survival signaling, cell migration, dysplasia and angiogenesis. While these functions can prevent initial establishment of tumors, they can also be hijacked by aggressive cancers to enhance tumor growth and metastasis. Thus, the role of the IL-22/IL-22R1 axis in cancer is complex and context-specific. Evidence of IL-22 involvement manifests as dysregulation of IL-22 expression and signaling in patients with many common cancers including those of the gut, skin, lung and liver. Unlike other cancer-associated cytokines, IL-22 has restricted tissue specificity as its unique receptor IL-22R1 is exclusively expressed on epithelial and tissue cells, but not immune cells. This makes it an attractive target for therapy as there is potential achieve anti-tumor immunity with fewer side effects. This review summarizes current findings on functions of IL-22 in association with general mechanisms for tumorigenesis as well as specific contributions to particular cancers, and ponders how best to approach further research in the field. [Copyright &y& Elsevier]

Abstract: Background: IL-20 is a pleiotrophic member of the IL-10 family and plays a role in skin biology and the development of haematopoietic cells. Recently, IL-20 has been demonstrated to have potential anti-angiogenic effects in non-small cell lung cancer (NSCLC) by down regulating COX-2. Methods: The expression of IL-20 and its cognate receptors (IL-20RA/B and IL-22R1) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of this family was examined in normal bronchial epithelial and NSCLC cell lines. Furthermore, the effect of IL-20 on VEGF family members was examined. Results: The expression of IL-20 and its receptors are frequently dysregulated in NSCLC. IL-20RB mRNA was significantly elevated in NSCLC tumours (p <0.01). Protein levels of the receptors, IL-20RB and IL-22R1, were significantly increased (p <0.01) in the tumours of NSCLC patients. IL-20 and its receptors were found to be epigenetically regulated through histone post-translational modifications and DNA CpG residue methylation. In addition, treatment with recombinant IL-20 resulted in decreased expression of the VEGF family members at the mRNA level. Conclusions: This family of genes are dysregulated in NSCLC and are subject to epigenetic regulation. Whilst the anti-angiogenic properties of IL-20 require further clarification, targeting this family via epigenetic means may be a viable therapeutic option in lung cancer treatment. [Copyright &y& Elsevier]

Background & Aims: Interleukin-22 (IL-22) is a Th17-related cytokine within the IL-10 family and plays an important role in host defense and inflammatory responses in orchestration with other Th17 cytokines. IL-22 exerts its functions in non-immune cells as its functional receptor IL-22R1 is restricted in peripheral tissues but not in immune cells. It was recently found that IL-22 serves as a protective molecule to counteract the destructive nature of the T cell-mediated immune response to liver damage. However, it is currently unknown whether IL-22 has an effect on lipid metabolism in the liver. Methods: In this study, we demonstrate that IL-22 alleviates hepatic steatosis induced by high fat diet (HFD). Results: Administration of recombinant murine IL-22 (rmIL-22) was able to stimulate STAT3 phosphorylation in HepG2 cells and mouse liver. The activation of STAT3 by rmIL-22 was reduced by the over-expression of a dominant negative IL-22R1. Within hours after rmIL-22 treatment, the expression of lipogenesis-related genes including critical transcription factors and enzymes for lipid synthesis in the liver was significantly down-regulated. The levels of triglyceride and cholesterol in the liver were significantly reduced by long-term treatment of rmIL-22 in C57BL/6 and ob/ob mice fed with HFD. The HFD-induced increases of ALT and AST in ob/ob mice were ameliorated by rmIL-22 treatment. In addition, the expression of fatty acid synthase and TNF-α in the liver was decreased by long-term rmIL-22 administration. Conclusions: Collectively, these data indicate that IL-22, in addition to its known functions in host defense and inflammation, has a protective role in HFD-induced hepatic steatosis via its regulation on lipid metabolism in the liver. [Copyright &y& Elsevier]