Abstract 14124: MyD88 - A Key Factor in the Anti-Apoptotic Role of IL-10 in Cardiomyocytes
Heart failure subsequent to a variety of etiologies is generally associated with an increase in pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), which is also known to cause apoptosis. In heart failure, subsequent to myocardial infarction, there is an increase in TNF-α and a decrease in anti-inflammatory protein, interleukin-10 (IL-10). In isolated cardiomyocytes, IL-10 has been shown to antagonize the pro-apoptotic effect of TNF-α. Although the anti-apoptotic action of IL-10 in cardiomyocytes is now generally accepted, its molecular basis is not yet well understood. We assumed that protective effect of IL-10 might be regulated through an innate defense system, thus its molecular mechanism is possibly preserved by TLR's innate signaling. Hence, we studied the role of Toll-like Receptor 4 (TLR4) and its downstream signals in the survival of adult cardiomyocytes in presence of IL-10. In IL-10 stimulated cardiomyocytes, TLR4 expression followed the upregulation of myeloid differentiation primary gene 88 (MyD88). MyD88 activation led to IRF3 dimerization and phosphorylation further augmented IL-1β translational activity. Degradation of Ikk suggested that Ikkβ is an activating kinase for IRF3-regulated NF-κB activation and its subunit protein p65 phosphorylation resulted in NF-κBp65 nuclear translocation. This in turn led to activation of Bcl-xL which attenuated the proteolytic activity of Caspase3 and PARP cleavage. Inhibition of MyD88 by pre-treatment of cardiomyocytes with MyD88 inhibitor and subsequent blunting of TLR4 expression emphasizes that TLR4 activation requires MyD88 adaptor molecule in execution of its downstream signals. Abrogation of MyD88 activity inhibited IRF3-dependent IL-1β production and NFκBp65 phosphorylation induced by IL-10. We also noticed a significant decrease in Bcl-xL expression leading to PARP cleavage resulting from inhibition of MyD88 activity. Our study suggests that anti-apoptotic function of IL-10 through TLR4 activation requires MyD88 for cardiomyocyte survival. Thus, MyD88 is a key signaling molecule in the TLR4 innate signaling pathway, which determines the ultimate effect of IL-10 in the induction of cardiomyocyte survival or apoptosis.
- © 2011 by American Heart Association, Inc.