Toll-like receptor 2 dominance over Toll-like receptor 4 in stressful conditions for its detrimental role in the heart

It has been suggested that Toll-like receptor (TLR)4 promotes IL-10-mediated cardiac cell survival, whereas another receptor, TLR2, from the same family, is detrimental. Here, we examined the interactive role of these two innate signaling molecules under stressful conditions, including IL-10 knockout (IL-10–/–) mice, global ischemia-reperfusion (I/R) injury in rat hearts, and in vitro short hairpin RNA experimental models in the presence or absence of IL-10 (10 ng/ml). Circulating and myocardial levels of TNF-α as well as apoptosis and fibrosis were higher in IL-10–/– mice. The increase in TLR2 in IL-10–/– hearts indicated its negative regulation by IL-10. Ex vivo I/R also caused a marked upregulation of TLR2 and TNF-α as well as apoptotic and fibrotic signals. However, a 40-min reperfusion with IL-10 triggered an increase in TLR4 expression and improved recovery of cardiac function. The increase in IL-1 receptor-associated kinase (IRAK)-M and IRAK-2 activity during I/R injury suggested their role in TLR2 signaling. In vitro inhibition of TLR4 activity as a consequence of RNA inhibition-mediated suppression of myeloid differentiation gene (MyD)88 suggested MyD88-dependent activation of TLR4. The inclusion of IL-10 during reperfusion also downregulated the expression of IRAK-2, TNF-α receptor-associated factor 1-interacting protein (TRAIP) and apoptotic signals, caspase-3, and the Bax-to-Bcl-xL ratio. IL-10 reduced the TNF-...
Source: AJP: Heart and Circulatory Physiology - Category: Cardiology Authors: Tags: ARTICLES Source Type: research