Increased levels of myocardial IκB-α 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 kappa B-a (I kappa B-alpha), releasing nuclear factor-kappa B (NF-kappa B) to activate TNF-alpha gene transcription. We hypothesized that LPS induces supranormal synthesis of myocardial I kappa B-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 I kappa B-alpha protein levels, activation of NF-kappa B, and increased TNF-alpha production. These events were followed by myocardial contractile depression. After the initial decrease in myocardial I kappa B-alpha, I kappa B-alpha protein levels rebounded to a level greater than control levels by 24 h. Dexamethasone pretreatment similarly increased myocardial I kappa B-alpha protein levels. In rats pretreated with either LPS or dexamethasone, myocardial I kappa B-alpha protein levels remained similar to control levels after LPS challenge. The preserved level of myocardial I kappa B-alpha protein was associated with diminished NF-kappa B activation, attenuated myocardial TNF-alpha production, and improved cardiac contractility. We conclude that LPS and dexamethasone upregulate myocardial I kappa B-alpha protein expression and that an increased level of myocardial I kappa B-alpha protein may promote cardiac tolerance to LPS by inhibition of NF-kappa B intranuclear translocation and myocardial TNF-alpha production.