Crosstalk between Toll‐like Receptor 4 and Interleukin 10 in Cardiomyocyte Survival

Abstract

Protective role of IL‐10 may be regulated through its innate signaling via activation of Patterns Recognition Receptors such as Toll‐like receptors (TLRs). Innate responses of IL‐10 through TLRs have not been fully described. In the present study, effects of IL‐10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival were examined. IL‐10 significantly activated the expression of co‐receptor CD14, TLR4 and Myeloid differentiation gene factor 88 (MyD88). Activation of TLR4 led to the translocation of the Interferon regulatory factor 3 (IRF3) into the nucleus. Phosphorylation of IRF3 enhanced mRNA synthesis for IL‐1β but not TNF‐α and was elevated even after removal of IL‐10. IRF3‐regulated NF‐κB activation and phosphorylation of p65 was also seen. Concomitantly, an increase in anti‐apoptotic Bcl‐xL activity inhibited Bax and proteolytic activity of caspase‐3 on PARP cleavage. An Inhibition of IL‐10 receptor completely attenuated the TLR4 expression suggesting that TLR4 and IL‐10 interact via receptor activation in the maintenance of cardiomyocyte homeostasis. On the other hand, when we inhibited MyD88 there was no increase in TLR4, IRF3, NF‐κB p65 and Bcl‐xL activity instead there was an increase in TNF‐α, Bax and PARP activity. Our data suggests that TLR4 and MyD88 play a crucial role in the anti‐apoptotic function of IL‐10 in cardiomyocytes.(Supported by CIHR)