Increased levels of myocardial IkappaB-alpha protein promote tolerance to endotoxin.
Endotoxin [lipopolysaccharide (LPS)] causes tumor necrosis factor-alpha (TNF-alpha)-mediated myocardial contractile depression. Tolerance to the cardiac toxicity of LPS can be induced by a prior exposure to LPS or by pretreatment with glucocorticoids. The mechanisms by which the myocardium acquires tolerance to LPS remain unknown. LPS causes phosphorylation and degradation of inhibitory kappaB-alpha (IkappaB-alpha), releasing nuclear factor-kappaB (NF-kappaB) to activate TNF-alpha gene transcription. We hypothesized that LPS induces supranormal synthesis of myocardial IkappaB-alpha protein and thus renders the myocardium tolerant to subsequent LPS. Rats were challenged with LPS after pretreatment with LPS, dexamethasone, or saline. In saline-pretreated rats, LPS caused a rapid decrease in myocardial IkappaB-alpha protein levels, activation of NF-kappaB, and increased TNF-alpha production. These events were followed by myocardial contractile depression. After the initial decrease in myocardial IkappaB-alpha, IkappaB-alpha protein levels rebounded to a level greater than control levels by 24 h. Dexamethasone pretreatment similarly increased myocardial IkappaB-alpha protein levels. In rats pretreated with either LPS or dexamethasone, myocardial IkappaB-alpha protein levels remained similar to control levels after LPS challenge. The preserved level of myocardial IkappaB-alpha protein was associated with diminished NF-kappaB activation, attenuated myocardial TNF-alpha production, and improved cardiac contractility. We conclude that LPS and dexamethasone upregulate myocardial IkappaB-alpha protein expression and that an increased level of myocardial IkappaB-alpha protein may promote cardiac tolerance to LPS by inhibition of NF-kappaB intranuclear translocation and myocardial TNF-alpha production.
Shames
B D
BD
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Meldrum
D R
DR
Selzman
C H
CH
Pulido
E J
EJ
Cain
B S
BS
Banerjee
A
A
Harken
A H
AH
Meng
X
X
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004361:Drug Tolerance; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000494:pharmacology; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone