Abstract 8603: Expression of Human Interleukine-37 Protects Mouse Heart Against Ischemic Injury Through Suppression of Monocyte Chemoattractant Protein-1-Mediated Mononuclear Cell Accumulation

Abstract

Myocardial inflammatory response to ischemia, involving up-regulated chemokine expression and leukocyte accumulation, contributes to the mechanism of myocardial injury and cardiac dysfunction. IL-37 is a new human cytokine and has an anti-inflammatory function. Currently, it is unknown whether IL-37 suppresses myocardial inflammatory response to ischemia. We tested the hypothesis that expression of human IL-37 in mouse protects the heart against ischemic injury and LV dysfunction through suppression of the myocardial inflammatory response. The purposes of this study were to determine: 1) the effect of expression of human IL-37 transgene on myocardial injury in mice after coronary artery ligation, 2) whether IL-37 suppresses myocardial chemokine expression and leukocyte accumulation following ischemia and 3) whether IL-37 modulates the inflammatory response of cardiac vascular endothelial cells (CVECs) to in vitro pro-inflammatory stimulation. Methods and results: IL-37 Tg and WT mice were subjected to left anterior descending coronary artery ligation. In addition, CVECs isolated from IL-37 Tg and WT mice were stimulated with TLR2 and TLR4 agonists. Expression of IL-37 markedly reduced infarct size and improved LV function. The protective effects of IL-37 were associated with reduced IKK phosphorylation, NF-κB intranuclear translocation, MCP-1 production and mononuclear cell accumulation in the ischemic myocardium. In WT mice, neutralization of MCP-1 or MCP-1 KO reduced mononuclear cell accumulation, infarct size and LV function deficit. Further, prior depletion of monocytes resulted in infarct size reduction and LV function improvement in WT mice. In vitro studies in mouse CVECs found that expression of IL-37 suppressed NF-κB activation and MCP-1 production induced by stimulation of TLR2 or TLR4. Conclusion: This study demonstrates that IL-37 protects the heart against ischemic injury and LV dysfunction through suppression of MCP-1 production and the resultant mononuclear cell accumulation. These findings suggest that this novel anti-inflammatory cytokine has a therapeutic potential for the regulation of myocardial inflammatory response to ischemia and for protection against ischemic myocardial injury.