Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium.
We have previously reported that induction of nuclear factor-kappa B (NF-kappa B) occurs in a biphasic manner in postischemic myocardium. Because interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric-oxide synthase (iNOS) contain kappa B-response elements, and since transforming growth factor-beta 1 (TGF-beta 1) down-modulates both cytokine and iNOS expression, we studied their temporal expression during myocardial ischemia/reperfusion (I/R). Northern and Western analyses showed low levels of IL-6 and no signal for IL-1 beta, TNF-alpha and iNOS under basal conditions. Their expression rose significantly over sham-operated controls by 1 h reperfusion, and persisted high for various periods. Under basal conditions, low levels of TGF-beta 1 were detected, which rose significantly at 3 h reperfusion, and remained high until 24 h reperfusion. Administration of diethyldithiocarbamate (DDC) inhibited induction of NF-kappa B and concomitantly the expression of IL-1 beta, IL-6, TNF-alpha as well as iNOS. However, expression of TGF-beta was not altered. Our results indicate that ischemia/reperfusion induces NF-kappa B, and upregulates kappa B-response genes. Administration of DDC inhibits NF-kappa B levels, and attenuates expression of inflammatory cytokines and iNOS.
Chandrasekar
B
B
Division of Cardiology, University of Texas Health Science Center, San Antonio 78284-7872, USA.
Streitman
J E
JE
Colston
J T
JT
Freeman
G L
GL
D000818:Animals; D015152:Blotting, Northern; D016207:Cytokines / Q000378:metabolism*; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction; D007150:Immunohistochemistry; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000276:immunology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011921:Rats, Inbred WKY
D016207:Cytokines; D016328:NF-kappa B; D004050:Ditiocarb; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat