Role of TLR-8 in the activation of nuclear factor kappa B by oxidative stress in cardiac myocytes

Growing evidence from patients with heart failure and from experimental ani mal models implicates effecters of innate immunity in the pathogenesis of t his syndrome. The expression of the innate immunity signaling protein, Toll -like receptor 4 (TLR4), is increased in cardiac myocytes in situ and in fa iling myocardium, but the mechanism by which TLRs may be activated in the f ailing heart remains unclear. We report that TLR2, which is expressed in ca rdiac myocytes, participates in the response of these cells to oxidative st ress, a major contributor to the pathogenesis of cardiac dysfunction. Hydro gen peroxide increased nuclear factor kappaB (NF-kappaB) activation in Chin ese hamster ovary fibroblasts that overexpress TLR2 but not in normal or TL R4-overexpressing Chinese hamster ovary cells, an effect that was abrogated by an alpha -TLR2 antibody. In neonatal rat ventricular myocytes, the alph a -TLR2 antibody inhibited hydrogen peroxide-induced nuclear translocation of NF-kappaB and activator protein-1 (AP-1), Inhibition of TLR2 had no effe ct on tumor necrosis factor alpha -induced NF-kappaB or AP-1 activation, on the DNA binding of the basal transcription factor Oct-1, or on hydrogen pe roxide-induced phosphorylation of p38 MAP kinase. Importantly, oxidative st ress-induced cytotoxicity was enhanced by blocking TLR2. Given the importan ce of cytotoxicity and apoptosis to the pathology of the ischemic heart, an anti-apoptotic effect of TLR2 in cardiac myocytes exposed to elevated leve ls of ROS may limit further cardiac dysfunction.