![]() Considering the intense interest in anti–IL-1 strategies for treatment of patients with myocardial infarction and heart failure ( 15), there is an urgent need to dissect the cell-specific actions of the cytokine in the healing infarct to design optimal therapeutic approaches. Moreover, proinflammatory cytokines, such as TNF-α and IL-1, may activate cytoprotective pathways reducing ischemic cardiomyocyte injury ( 12, 13) these protective actions may be, at least in part, responsible for the detrimental effects of TNF blockade in patients with heart failure ( 14). In addition to their role in clearance of the infarct from dead cells and matrix debris, inflammatory mediators released in the infarcted heart also stimulate expression of fibrogenic and angiogenic growth factors, thus setting the stage for scar formation. However, inflammatory cytokines and chemokines also transduce key reparative signals. Inflammatory cytokines in the infarcted heart may stimulate cardiomyocyte apoptosis ( 8, 9), exert negative inotropic actions accentuating systolic dysfunction ( 10), and induce expression of matrix-degrading proteases promoting dilative cardiac remodeling ( 11). Myocardial inflammation after infarction has both injurious and beneficial aspects. IL-1β expression is also markedly increased in myocardial infarcts ( 6) and drives the local inflammatory reaction ( 7) however, understanding its role in cardiac repair, remodeling, and postinfarction dysfunction is hampered by the cell biological complexity of infarctive injury. A double-blind clinical trial examining the effects of IL-1β inhibition on the incidence of new cardiovascular events in diabetic patients with high cardiovascular risk is currently in progress and will test the hypothesis that IL-1β is critically involved in progression and complications of atherosclerotic disease in human patients ( 5). IL-1 is markedly upregulated in atheromatous lesions and may mediate inflammatory changes in diet-induced atherosclerosis ( 4), accelerating atherosclerotic disease and promoting plaque instability. A growing body of evidence suggests an important role for IL-1 in the pathogenesis of cardiovascular disease ( 3). IL-1 may orchestrate fibroblast responses in the infarct early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.Īs the prototypical proinflammatory cytokine, IL-1 drives local and systemic inflammation after injury and is critically involved in the pathobiology of immune and inflammatory conditions ( 1, 2). The effects of IL-1 on TGF-β responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-β signaling. Moreover, IL-1β attenuated TGF-β–induced contractile activity of fibroblasts populating collagen pads, attenuated α-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1–dependent manner. Nonmyeloid CD11b − cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines their inflammatory activation was IL-1R1 dependent. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6C hi and Ly6C lo cells. Increased expression of IL-1R2 may serve to terminate IL-1–driven inflammation after infarction. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6C hi cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure.
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