Cytokines link Toll-like receptor 4 signaling to cardiac dysfunction after global myocardial ischemia

Ann Thorac Surg. 2008 May;85(5):1678-85. doi: 10.1016/j.athoracsur.2008.01.043.


Background: Although Toll-like receptor 4 (TLR4) has been implicated in the myocardial injury caused by regional ischemia/reperfusion, its role in the myocardial inflammatory response and in contractile dysfunction after global ischemia/reperfusion is unclear. Cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), contribute to the mechanism of myocardial dysfunction after global ischemia/reperfusion. We hypothesized that a TLR4-mediated cytokine cascade modulates myocardial contractile function after global ischemia/reperfusion. This study examined whether TLR4 regulates TNF-alpha and interleukin (IL)-1beta peptide production during global ischemia/reperfusion and whether TLR4 signaling influences postischemic cardiac function through TNF-alpha and IL-1beta.

Methods: Isolated hearts from wild-type mice, two strains of TLR4 mutants, TNF-alpha knockouts, and IL-1beta knockouts underwent global ischemia/reperfusion. Cardiac contractile function was analyzed, and myocardial nuclear factor-kappaB activity and TNF-alpha and IL-1beta levels were measured.

Results: In wild-type hearts, global ischemia/reperfusion induced nuclear factor-kappaB activation and the production of TNF-alpha and IL-1beta peptides. In TLR4-mutant hearts, these changes were significantly reduced and postischemic functional recovery was improved. Application of TNF-alpha and IL-1beta to TLR4-mutant hearts abrogated this improvement in postischemic functional recovery. Postischemic functional recovery also improved in TNF-alpha knockout and IL-1beta knockout hearts, as well as in wild-type hearts treated with TNF-binding protein or IL-1 receptor antagonist.

Conclusions: This study demonstrates that TLR4 signaling contributes to cardiac dysfunction after global ischemia/reperfusion. TLR4 signaling mediates the production of TNF-alpha and IL-1beta peptides, and these two cytokines link TLR4 signaling to postischemic cardiac dysfunction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gene Expression / genetics
  • Interleukin-1beta / blood*
  • Interleukin-1beta / genetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Mutant Strains
  • Myocardial Contraction / genetics*
  • Myocardial Reperfusion Injury / genetics*
  • Myocardium / metabolism
  • NF-kappa B / blood
  • RNA, Messenger / genetics
  • Signal Transduction / genetics*
  • Toll-Like Receptor 4 / genetics*
  • Tumor Necrosis Factor-alpha / blood*
  • Tumor Necrosis Factor-alpha / genetics


  • Interleukin-1beta
  • NF-kappa B
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha