P38 MAPK mediates myocardial proinflammatory cytokine production and endotoxin-induced contractile suppression.
Cardiac myocytes are capable of synthesizing tumor necrosis factor alpha (TNF-alpha), 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-alpha production; however, the extent to which this kinase contributes to endotoxin-induced contractile dysfunction, as well as TNF-alpha, IL-1alpha, IL-1beta, 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-alpha, IL-1alpha, IL-1beta, and IL-6 mRNA levels. To determine the relative effect of TNF-alpha in inducing IL-1alpha, IL-1beta, and IL-6 production, TNF-alpha was sequestered during endotoxin infusion, and TNF-alpha, IL-1beta, and IL-6 protein levels were measured. Interestingly, TNF-alpha sequestration alone significantly decreased myocardial IL-1beta and IL-6 production. We conclude that p38 MAPK is involved in endotoxin-induced myocardial contractile dysfunction and myocardial TNF-alpha production; however, p38 MAPK's involvement in IL-1 and IL-6 production may be indirectly mediated by TNF-alpha.
Wang
Meijing
M
Department of Surgery, Section of Cardiothoracic Surgery, Indiana Center for Vascular Biology and Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202, USA.
Sankula
Rajakumar
R
Tsai
Ben M
BM
Meldrum
Kirstan K
KK
Turrentine
Mark
M
March
Keith L
KL
Brown
John W
JW
Dinarello
Charles A
CA
Meldrum
Daniel R
DR
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis*; D004731:Endotoxins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D011725:Pyridines; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580