The interaction between myocardial depressant factors in endotoxemic cardiac dysfunction: role of TNF-alpha in TLR4-mediated ICAM-1 expression.
Multiple pro-inflammatory mediators contribute to cardiac dysfunction caused by bacterial lipopolysaccharide (LPS). The rapid TNF-alpha response is likely involved in the induction of down-stream myocardial depressant factors. Studies by our laboratory and others indicate an important role for ICAM-1 in endotoxemic cardiac dysfunction through leukocyte-independent mechanisms. The purpose of this study was to determine: whether ICAM-1 knockout improves cardiac function during endotoxemia and whether TLR4 and TNF-alpha regulate LPS-induced myocardial ICAM-1 expression.


RESULTS
Mice were treated with Escherichia coli LPS (0.5mg/kg iv). Myocardial ICAM-1 levels were analyzed by immunoblotting and left ventricular developed pressure (LVDP) was assessed by the Langendorff technique. In wild-type mice, peak ICAM-1 levels were observed at 4h when myocardial contractility was depressed. Myocardial contractility was improved following LPS in mice lacking functional TLR4, TNF-alpha or ICAM-1. TLR4 mutation abolished ICAM-1 expression with abrogation of precedent TNF-alpha response. Similarly, TNF-alpha knockout reduced myocardial ICAM-1 level following LPS treatment.


CONCLUSIONS
ICAM-1 contributes to the mechanism of endotoxemic cardiac dysfunction. TNF-alpha is involved in the regulation of myocardial ICAM-1 expression by TLR4.
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorando, USA.
Lihua
L
Ao
Yong
Y
Song
David A
DA
Fullerton
Charles A
CA
Dinarello
Xianzhong
X
Meng
D000818:Animals; D019446:Endotoxemia / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology; D009201:Myocardial Depressant Factor / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000276:immunology / Q000503:physiopathology
C090509:Icam1 protein, mouse; D009201:Myocardial Depressant Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1