Copyright © 2006, European Society of Cardiology
Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-
B dependent inflammatory response
Critical Care Research Laboratories, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6
* Corresponding author. Tel.: +1 604 806 8136; fax: +1 604 806 8351. Email address: kwalley{at}mrl.ubc.ca
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-
B)-Luciferase reporter plasmid, we found significantly increased NF-B transcriptional activity in response to TLR2, TLR4 and TLR5 activation in cardiomyocytes. Further, a chemical inhibitor of NF-B, pyrrolidine dithiocarbamate (PDTC), as well as transfection using a dominant negative form of IKKβ, 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-B, resulting in decreased contractility and a concerted inflammatory response.
KEYWORDS Infection/inflammation; Contractile function; Cytokines; Myocytes
Support: Canadian Institutes of Health Research. K.R. Walley is a Michael Smith Foundation for Health Research Distinguished Scholar. J.H. Boyd is an IMPACT Postdoctoral Fellow.
Time for primary review 15 days
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