Toll-like receptor stimulation in cardiornyoctes decreases contractility and initiates an NF-κB dependent inflammatory response

Objective: The transmembrane receptor family of Toll-like receptors (TLRs) may play a role in initiating early inflammatory and functional responses to danger signals arising from ischemia-reperfusion and inflammatory stimuli. We determined whether Toll-like receptors are expressed in cardiac tissue and whether stimulation with cognate ligands would result in a pro-inflammatory response and decreased cardiomyocyte contractility. Methods and results: We observed mRNA expression of TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9 in both whole heart tissue and a murine cardiomyocyte cell line (HL-1). Ligand activation of TLR2, TLR4 and TLR5, but not TLR3, TLR7 or TLR9, resulted in cardiomyocyte expression of the inflammatory cytokine IL-6, the chemokines KC and MIP-2, and the cell surface adhesion molecule ICAM-1. Activation of these Toll-like receptors was associated with decreased cardiomyocyte contractility. Using transfection of a nuclear factor kappa B (NF-kappa B)-Luciferase reporter plasmid, we found significantly increased NF-kappa B transcriptional activity in response to TLR2, TLR4 and TLR5 activation in cardiomyocytes. Further, a chemical inhibitor of NF-kappa B, pyrrolidine dithiocarbarnate (PDTC), as well as transfection using a dominant negative form of IKK beta, resulted in profound reduction of the TLR-initiated pro-inflammatory response. Conclusions: Cardiomyocytes express most known Toll-like receptors. Of these, TLR2, TLR4 and TLR5 signal via NF-kappa B, resulting in decreased contractility and a concerted inflammatory response. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.