Abstract 124: Postischemic Induction of IL-17 Signaling Promotes Necrotic and Apoptotic Cell Death in the Rat Heart Exposed to in Vivo Ischemia/Reperfusion Injury
Background. L-17A and IL-17F are pro-inflammatory cytokines, which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 effector proteins facilitate the recruitment of neutrophils to the site of inflammation and promote dismantling of the extracellular matrix to aid in neutrophil migration. IL-17 cytokines have recently attracted huge interest due to the pathogenic role of il-17 secreting T cells (Th17 cells) in diseases such as arthritis, multiple sclerosis and inflammatory bowel disease.
Aims. To investigate the role of IL-17 cytokines in myocardial ischemia/reperfusion injury (IRI).
Methods and Results. Expression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) was dramatically increased (>7 fold) in rat hearts exposed to in vivo IRI (30 minutes of ischemia and 2 hours reperfusion), as documented by affymetrix microarray analysis and confirmed by quantitative real-time PCR. Moreover, several IL-17 target genes were also upregulated following IRI, including KC (Cxcl1), Cxcl2, Cxcl3, Ccl2 (MCP-1), IL-1β, iNOS, IL-6, S100a8, S100a9, Ccr1, P-selectin, ICAM-1, MMP-8, MMP-9, Ptgs2, Timp1, lcn2, Cotl1 and Spsb1. In addition, IL-17A promoted the expression of KC and IL-6 in isolated cardiac mycoytes in a MAPK and PI(3)K dependent manner. IL-17A and IRI were found to have an additive effect on KC expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment following IRI. Although cardiac myocytes were found to express relatively low levels of IL-17A mRNA, IL-17F and IL-17RA were induced by IRI injury in these cells. Likewise, protein levels of both IL-17R and IL-17A were enhanced following in vivo IRI. Finally, intraperitoneal injection of IL-17 blocking antibody prior to in vivo IRI promoted postischemic hemodynamic recovery, minimized infarct size and reduced the extent of myocyte apoptosis.
Conclusions. IL-17 cytokines and their receptor are induced following myocardial IRI and promote myocyte necrosis and apoptosis. Strategies aimed at modulating the expression of IL-17 cytokines may be clinically useful to promote cell survival following IRI.
- © 2011 by American Heart Association, Inc.