|Title||Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response.|
|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Boyd, JH, Mathur, S, Wang, Y, Bateman, RM, Walley, KR|
|Date Published||2006 Dec 1|
|Keywords||Adult, Animals, Cell Line, Cell Size, Cells, Cultured, Cytokines, Echocardiography, Humans, I-kappa B Kinase, Intercellular Adhesion Molecule-1, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocarditis, Myocytes, Cardiac, NF-kappa B, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 3, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 9, Toll-Like Receptors, Transfection|
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-kappaB)-Luciferase reporter plasmid, we found significantly increased NF-kappaB transcriptional activity in response to TLR2, TLR4 and TLR5 activation in cardiomyocytes. Further, a chemical inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC), as well as transfection using a dominant negative form of IKKbeta, 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-kappaB, resulting in decreased contractility and a concerted inflammatory response.
|Alternate Journal||Cardiovasc. Res.|