Cytokines Link Toll-Like Receptor 4 Signaling to Cardiac Dysfunction After Global Myocardial Ischemia

Background Although Toll-like receptor 4 (TLR4) has been implicated in the myocardial injury caused by regional ischemia/reperfusion, its role in the myocardial inflammatory response and in contractile dysfunction after global ischemia/reperfusion is unclear. Cytokines, particularly tumor necrosis factor-α (TNF-α), contribute to the mechanism of myocardial dysfunction after global ischemia/reperfusion. We hypothesized that a TLR4-mediated cytokine cascade modulates myocardial contractile function after global ischemia/reperfusion. This study examined whether TLR4 regulates TNF-α and interleukin (IL)-1β peptide production during global ischemia/reperfusion and whether TLR4 signaling influences postischemic cardiac function through TNF-α and IL-1β. Methods Isolated hearts from wild-type mice, two strains of TLR4 mutants, TNF-α knockouts, and IL-1β knockouts underwent global ischemia/reperfusion. Cardiac contractile function was analyzed, and myocardial nuclear factor-κB activity and TNF-α and IL-1β levels were measured. Results In wild-type hearts, global ischemia/reperfusion induced nuclear factor-κB activation and the production of TNF-α and IL-1β peptides. In TLR4-mutant hearts, these changes were significantly reduced and postischemic functional recovery was improved. Application of TNF-α and IL-1β to TLR4-mutant hearts abrogated this improvement in postischemic functional recovery. Postischemic functional recovery also improved in TNF-α knockout and IL-1β knockout hearts, as well as in wild-type hearts treated with TNF-binding protein or IL-1 receptor antagonist. Conclusions This study demonstrates that TLR4 signaling contributes to cardiac dysfunction after global ischemia/reperfusion. TLR4 signaling mediates the production of TNF-α and IL-1β peptides, and these two cytokines link TLR4 signaling to postischemic cardiac dysfunction.