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

Abstract

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 STAT 3 (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 STAT 3 activation after IL ‐22 injection by Western blot analysis and immunostaining for phosphorylated STAT 3 in the heart and found that STAT 3 activation in heart tissue rapidly peaked after IL ‐22 injection. Coimmunostaining of phosphorylated STAT 3 and α‐actinin revealed that STAT 3 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 STAT 3, 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– STAT 3 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 STAT 3 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 STAT 3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

“…In this study, each stage of the p38 MAPK/macrophage/Fizz3 axis was intervened, and the results indicate that IL-22 protects DOX-induced cardiac injury by reducing cardiomyocyte apoptosis. While in a recent study, Takahashi et al reported that treatment with recombinant mouse IL-22 decreases multiple cardiac apoptosis markers expression in ischemia-reperfusion mice, which suggest that IL-22 plays a anti-apoptotic role in cardiac ischemia-reperfusion [ 48 ]. This result is inconsistent with our conclusion, one possible explanation is that, as a pluripotent cytokine, the microenvironment in which IL-22 is located determines its regulatory effect on apoptosis.…”

Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR‐383/RP105/AKT signalling pathway

“…Currently, the most effective way to save dying cardiomyocytes induced by acute myocardial infarction (AMI) is timely revascularization 1‐5 . However, re‐establishing blood to ischaemic area yields additional myocardial damages known as myocardial ischaemia/reperfusion (I/R) injury (MIRI) 1‐3 .…”

“…Currently, the most effective way to save dying cardiomyocytes induced by acute myocardial infarction (AMI) is timely revascularization 1‐5 . However, re‐establishing blood to ischaemic area yields additional myocardial damages known as myocardial ischaemia/reperfusion (I/R) injury (MIRI) 1‐3 . MIRI affects clinical efficacy of revascularization strategies and serves as an important factor in worsening heart structure and function 1‐3,6,7 .…”

“…[1][2][3] MIRI affects clinical efficacy of revascularization strategies and serves as an important factor in worsening heart structure and function. [1][2][3]6,7 Although programmed cell death that mainly contains necrosis, apoptosis and autophagy acts as the major pathogenesis in the development of MIRI, 3,8,9 it is now verified that pyroptosis-associated necrosis also plays important roles in MIRI. 6,7,10 Pyroptosis acts as a pro-inflammatory programmed cell death and was characterized as a NLRP3-caspase-1-dependent response during MIRI.…”

“…[1][2][3][4][5] However, re-establishing blood to ischaemic area yields additional myocardial damages known as myocardial ischaemia/ reperfusion (I/R) injury (MIRI). [1][2][3] MIRI affects clinical efficacy of revascularization strategies and serves as an important factor in worsening heart structure and function. [1][2][3]6,7 Although programmed cell death that mainly contains necrosis, apoptosis and autophagy acts as the major pathogenesis in the development of MIRI, 3,8,9 it is now verified that pyroptosis-associated necrosis also plays important roles in MIRI.…”