Increased levels of myocardial IκB-α protein promote tolerance to endotoxin.

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