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)-1 beta, and nitric oxid e (NO) may play a role in lipopolysaccharide (LPS)-induced cardiac depressi on. Toll-like receptor-4 (TLR-4) mediates the cytokine response to LPS in i mmune cells. TLR-4 also is expressed in human and murine myocardial tissue. Therefore, the hypothesis that LPS induces proinflammatory cytokines in th e 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- 1 beta mRNA in C3HeB/FeJ mice. The response in C3H/HeJ mice was blunted and delayed. Myocardial TNF-alpha and IL-1 beta protein levels were higher in C3HeB/FeJ mice, as were inducible NO synthase protein and NO production. Ac tivation of myocardial NF-kappaB was observed within 30 min in C3HeB/FeJ mi ce but not in C3H/HeJ mice. These findings suggest that myocardial TLR-4 is involved in signaling cytokine production within the heart during endotoxi c shock.