title: Cytokines link Toll-like receptor 4 signaling to cardiac dysfunction after global myocardial ischemia.
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.
authors.affiliation: Department of Surgery, University of Colorado Denver, Denver, Colorado 80262, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cha
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.forename: Ning
authors.initials: N
authors.lastname: Zou
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000818:Animals; D015870:Gene Expression / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha