Background-Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. Methods and Results-Constitutive expression of TNF-␣ and not IL-1␤ was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-␣ in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-␣ in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-␣. Conclusions-Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-␣. We suggest that mast cell-derived TNF-␣ may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophilinduced injury. (Circulation. 1998;98:699-710.)

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The proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI؊/؊ mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI ؊/؊ mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1␤ stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction. Infarct healing is dependent on induction of an inflammatory cascade that ultimately results in formation of a collagen-based scar.1 The healing response is closely intertwined with ventricular remodeling, a complex process that involves both the infarcted and noninfarcted myocardium resulting in dilation, hypertrophy, and enhanced sphericity of the ventricle. 2 The extent of remodeling after infarction is an important predictor of mortality and adverse outcome after infarction, 3,4 and depends on the size of the infarct and on the mechanical and structural characteristics of the healing wound. Inflammatory mediators may be critically involved in the pathogenesis of cardiac remodeling by modulating cell behavior in the infarcted heart and by regulating extracellular matrix metabolism. 5-7Interleukin (IL)-1 plays a central role in regulating inflammatory and fibrotic responses by inducing synthesis of proinflammatory mediators, by promoting leukocyte infiltration and activation, and by modulating fibroblast function. IL-1 binds to two distinct receptors on the cell membrane: the type I IL-1 receptor (IL-1RI) is sufficient to mediate all IL-1 actions, 8 whereas the type II receptor (IL-1RII) serves as a decoy target, 9 trapping and scavenging IL-1 molecules, 10 thus reducing IL-1 concentration available for interaction with the IL-1RI signa...

Background-Previous work from our laboratory demonstrated that interleukin (IL)-6 plays a potentially critical role in postreperfusion myocardial injury and is the major cytokine responsible for induction of intracellular adhesion molecule (ICAM)-1 on cardiac myocytes during reperfusion. Myocyte ICAM-1 induction is necessary for neutrophil-associated myocyte injury. We have previously demonstrated the induction of IL-6 in the ischemic myocardium, and the current study addresses the cells of origin of IL-6. Methods and Results-In the present study, we combined Northern blot analysis and in situ hybridization to demonstrate IL-6 gene expression in cardiac myocytes. Isolated ventricular myocytes were stimulated with tumor necrosis factor-␣, IL-1␤, lipopolysaccharide, preischemic lymph, and postischemic lymph. Unstimulated myocytes showed no significant IL-6 mRNA expression. Myocytes stimulated with preischemic lymph showed minimal or no IL-6 mRNA expression, whereas myocytes stimulated with tumor necrosis factor-␣, IL-1␤, lipopolysaccharide, or postischemic lymph showed a strong IL-6 mRNA induction. Northern blot with ICAM-1 probe revealed ICAM-1 expression under every condition that demonstrated IL-6 induction. We then investigated the expression of IL-6 mRNA in our canine model of ischemia and reperfusion. Cardiac myocytes in the viable border zone of a myocardial infarction exhibited reperfusion-dependent expression of IL-6 mRNA within 1 hour after reperfusion. Mononuclear cells infiltrate the border zone and express IL-6 mRNA. Conclusions-Isolated cardiac myocytes produce IL-6 mRNA in response to several cytokines as well as postischemic cardiac lymph. In addition to its production by inflammatory cells, we demonstrate that IL-6 mRNA is induced in myocytes in the viable border zone of a myocardial infarct. The potential roles of IL-6 in cardiac myocytes in an infarct border are discussed. (Circulation. 1999;99:546-551.)