| Title | Cytokines link Toll-like receptor 4 signaling to cardiac dysfunction after global myocardial ischemia. | | Author(s) | Cha J, Wang Z, Ao L, Zou N, Dinarello CA, Banerjee A, Fullerton DA, Meng X | | Institution | Department of Surgery, University of Colorado Denver, Denver, Colorado 80262, USA. | | Source | Ann Thorac Surg 2008 May; 85(5):1678-85. | | MeSH | Animals
Gene Expression
Interleukin-1beta
Male
Mice
Mice, Inbred Strains
Mice, Knockout
Mice, Mutant Strains
Myocardial Contraction
Myocardial Reperfusion Injury
Myocardium
NF-kappa B
RNA, Messenger
Signal Transduction
Toll-Like Receptor 4
Tumor Necrosis Factor-alpha
| | Abstract | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
| | PubMed ID | 18442564 |
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