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P38 MAPK Mediates Myocardial Proinflammatory Cytokine Production and Endotoxin-Induced Contractile Suppression

2004; Lippincott Williams & Wilkins; Volume: 21; Issue: 2 Linguagem: Inglês

10.1097/01.shk.0000110623.20647.aa

1540-0514

Meijing Wang, Rajakumar Sankula, Ben M. Tsai, Kirstan K. Meldrum, Mark W. Turrentine, Keith L. March, John W. Brown, Charles A. Dinarello, Daniel R. Meldrum,

Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Cardiac myocytes are capable of synthesizing tumor necrosis factor α (TNF-α), interleukin-1, and interleukin-6 (IL-1 and IL-6). p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant-stress-induced myocardial TNF-α production; however, the extent to which this kinase contributes to endotoxin-induced contractile dysfunction, as well as TNF-α, IL-1α, IL-1β, and IL-6 production, in a bloodless model of endotoxin-induced myocardial dysfunction is unknown. Isolated rat hearts were perfused (Langendorff), and myocardial contractile function continuously recorded, during direct antegrade endotoxin infusion, with and without prior p38 MAPK inhibition. Ventricular p38 MAPK activation (phospho-p38 MAPK Western), cytokine mRNA (RT-PCR), and protein (ELISA) were determined. Endotoxin resulted in progressive decline in left ventricular developed pressure and coronary flow that was attenuated with prior p38 MAPK inhibition (SB 203580). p38 MAPK inhibition significantly decreased endotoxin-induced cardiac TNF-α, IL-1α, IL-1β, and IL-6 mRNA levels. To determine the relative effect of TNF-α in inducing IL-1α, IL-1β, and IL-6 production, TNF-α was sequestered during endotoxin infusion, and TNF-α, IL-1β, and IL-6 protein levels were measured. Interestingly, TNF-α sequestration alone significantly decreased myocardial IL-1β and IL-6 production. We conclude that p38 MAPK is involved in endotoxin-induced myocardial contractile dysfunction and myocardial TNF-α production; however, p38 MAPK's involvement in IL-1 and IL-6 production may be indirectly mediated by TNF-α.