INDUCTION OF INTERLEUKIN-6 SYNTHESIS IN THE MYOCARDIUM - POTENTIAL ROLE IN POSTREPERFUSION INFLAMMATORY INJURY

Background Neutrophil-induced injury of myocardial cells requires the expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyt e surface and is mediated by ICAM-1-CD11b/CD18 adhesion. We have previ ously shown that interleukin-6 (IL-6) cytokine activity, present in ca rdiac lymph, induces ICAM-1 on isolated cardiac myocytes. Furthermore, in previous in vivo studies, we have also shown ICAM-1 mRNA induction in the myocardium within the first hour of reperfusion in the previou sly ischemic viable zone. We hypothesized that induction of IL-6 synth esis in the myocardium was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induct ion of ICAM-1 on myocardial cells. Methods and Results In this study, cloned canine IL-6 cDNA was used as a molecular probe to study the reg ulation of IL-6 in an awake canine model of myocardial ischemia and re perfusion. IL-6 mRNA was induced in ischemic and reperfused segments o f myocardium preferentially in segments previously exposed to severe i schemia. Peak levels of IL-6 mRNA were reached within 3 hours of reper fusion. At the same time, IL-6 mRNA and ICAM-1 mRNA were found in the same myocardial segments. In contrast to hearts that were ischemic for 1 hour and reperfused for 3 hours, nonreperfused hearts after 4 hours of persistent ischemia demonstrated minimal induction of ICAM-1 or IL -6 despite similar degrees of injury and blood flow reductions during ischemia. After 24 hours of persistent ischemia, levels of IL-6 mRNA w ere comparable to those observed in hearts that were ischemic for 1 ho ur and subsequently reperfused for 24 hours. Conclusions Our results d emonstrate induction of IL-6 mRNA in the myocardium and that this synt hesis is accelerated by reperfusion. Evidence is also provided to show that peak IL-6 mRNA precedes that of ICAM-1 mRNA. These findings are compatible with our hypothesis that IL-6 is important in the induction of ICAM-1 in the area of ischemia. In addition, these studies suggest that the necessary factors to promote adhesive interactions between t ransmigrated neutrophils and cardiac myocytes are present in reperfuse d myocardium.