In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4.
Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) may play a role in lipopolysaccharide (LPS)-induced cardiac depression. Toll-like receptor-4 (TLR-4) mediates the cytokine response to LPS in immune cells. TLR-4 also is expressed in human and murine myocardial tissue. Therefore, the hypothesis that LPS induces proinflammatory cytokines in the heart via TLR-4 was tested. C3H/HeJ (TLR-4 deficient) and C3HeB/FeJ mice were studied. LPS induced a robust increase in myocardial TNF-alpha and IL-1beta mRNA in C3HeB/FeJ mice. The response in C3H/HeJ mice was blunted and delayed. Myocardial TNF-alpha and IL-1beta protein levels were higher in C3HeB/FeJ mice, as were inducible NO synthase protein and NO production. Activation of myocardial NF-kappaB was observed within 30 min in C3HeB/FeJ mice but not in C3H/HeJ mice. These findings suggest that myocardial TLR-4 is involved in signaling cytokine production within the heart during endotoxic shock.
Baumgarten
G
G
Department of Medicine, Cardiology Section, Winters Center for Heart Failure Research, and Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas, USA.
Knuefermann
P
P
Nozaki
N
N
Sivasubramanian
N
N
Mann
D L
DL
Vallejo
J G
JG
D000818:Animals; D029721:Drosophila Proteins; D004731:Endotoxins / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D029721:Drosophila Proteins; D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse