Promoting effects of IL-23 on myocardial ischemia and reperfusion are associated with increased expression of IL-17A and upregulation of the JAK2-STAT3 signaling pathway

Abstract

Interleukin (IL)-23, as a novel pro-inflammatory cytokine, is important in several inflammatory diseases, including myocardial ischemia and reperfusion (I/R) injury, however, the underlying mechanism remains to be elucidated. The present study was designed to investigate the specific role of IL-23 in myocardial I/R injury, and whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway, one of the important downstream signaling pathways of IL-23, and the IL-17A downstream pro-inflammatory cytokine, were involved. Anesthetized rats underwent different treatments with adenovirus (Ad) vectors (Ad-GFP, Ad-IL-23, Anti-IL-23 or Ad-IL-23+AG490) and were then subjected to ischemia for 30 min prior to 4 h reperfusion. The effects of the upregulation and downregulation of IL-23 on myocardial injury, inflammatory responses in myocardial tissue, and myocardial apoptosis were measured accordingly. In addition, the levels of phosphorylated (P-)JAK2 and P-STAT3 were measured to assess the activity of the JAK2-STAT3 signaling pathway. The results demonstrated that there was an increased expression of IL-23 in the myocardial tissue exposed to myocardial I/R injury (P<0.05). The upregulation of IL-23 significantly increased the infarct size and the expression levels of lactate dehydrogenase and creatine kinase (P<0.05). The upregulation of IL-23 significantly increased inflammatory responses, as reflected by the high expression levels of IL-17A, IL-6, tumor necrosis factor-α in the myocardial tissues (P<0.05). Furthermore, the upregulation of IL-23 significantly facilitated the decrease in the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein ratio, and the increases in the myocardial apoptotic index and expression of caspase-3 induced by myocardial I/R (P<0.05). IL-23 also activated the JAK2-STAT3 signaling pathway, upregulating the expression levels of P-JAK2 and P-STAT3 in the myocardial tissues (P<0.05). Treatment with AG490, an inhibitor of JAK2-STAT3, partially attenuated the pro-inflammatory and pro-apoptotic effects of IL-23 (P<0.05). The results of the present study suggested that IL-23 aggravated myocardial I/R injury by promoting inflammatory responses and myocardial apoptosis, which may be associated with high expression levels of IL-17A and upregulation of the JAK2-STAT3 signaling pathway.