| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 5897204 | Cytokine | 2013 | 11 Pages |
Toll-like receptors (TLRs) are important in a variety of inflammatory diseases including acute cardiac disorders. TLR4 innate signaling regulates the synthesis of anti-inflammatory cytokine, interleukin-10 (IL-10) upon TLR4 agonists' re-stimulation. Anti-apoptotic action of IL-10 in cardiac dysfunction is generally accepted but its protective mechanism through TLR4 is not yet understood. We studied the effect of IL-10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival. IL-10 caused a significant increase in the expression of CD14, MyD88 and TLR4. TLR4 activation 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 stimulation. Furthermore, degradation of inhibitory kappa B (IκB) kinase (Ikk) suggested that IκBβ was the main activating kinase for IRF3-regulated NF-κB activation and phosphorylation of p65. Phosphorylated NF-κB p65 was translocated into the nucleus. Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage. An inhibition of MyD88, modulated the above listed responses to IL-10 as there was a decrease in TLR4 and IRF3 and an increase in TNF-α mRNA. This was associated with a decrease in NF-κB p65, Bcl-xL mRNA and protein levels as well as there was an activation of Bax and PARP cleavage independent of caspase 3 activation. These data in cardiomyocytes suggest that IL-10 induced anti-apoptotic signaling involves upregulation of TLR4 through MyD88 activation.
⺠Besides known TLR4 agonists such as LPS, IL-10 can also activate MyD88 dependent TLR4 signaling. ⺠IRF3 phosphorylation leads to IL-1β synthesis and regulates p65 phosphorylation, a subunit of NF-κB. ⺠Ikk degradation into IκB enhances pro-survival protein Bcl-xL via NF-κB p65 activation. ⺠MyD88 inhibition obliterated IL-10 induced TLR4 innate signaling leading to apoptosis. ⺠MyD88 is a key factor in anti-apoptotic role of IL-10 in cardiomyocyte survival.
