Interleukin‐22 Directly Activates Myocardial STAT3 (Signal Transducer and Activator of Transcription‐3) Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury

BACKGROUND: Interleukin (IL)‐22, a member of the IL‐10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL‐22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription‐3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS: We evaluated the STAT3 activation after IL‐22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL‐22 injection. Coimmunostaining of phosphorylated STAT3 and α‐actinin revealed that STAT3 activation occurred in cardiomyocytes after IL‐22 administration. In heart tissue from intact mice, real‐time PCR demonstrated significant expression of IL‐22 receptor subunit 1, and coimmunostaining of IL‐22 receptor subunit 1 and α‐actinin showed IL‐22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL‐22 activated STAT3, and we detected IL‐22 receptor subunit 1 expression. Overall, these results indicated that IL‐22 directly activated the myocardial IL‐22‐receptor subunit 1–STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS‐treated mice, IL‐22‐treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL‐22‐treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS: Our present findings suggest that IL‐22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.