Effect of acetylsalicylic acid on endogenous IκB kinase activity in lung epithelial cells

The anti-inflammatory effect of acetylsalicylic acid (ASA) has been thought to be secondary to the inhibition of prostaglandin synthesis. Because doses of ASA necessary to treat chronic inflammatory diseases are much higher than those needed to inhibit prostaglandin synthesis, a prostaglandin-independent pathway has been emerging as the new anti-inflammatory mechanism of ASA. Here, we examined the effect of ASA on the interleukin (IL)-1β- and tumor necrosis factor (TNF)-α-induced proinflammatory cytokine expression and evaluated whether this effect is closely linked to the nuclear factor (NF)-κB/IκB-α pathway. A high dose of ASA blocked IL-1β- and TNF-α-induced TNF-α and IL-8 expression, respectively. ASA inhibited TNF-α-induced activation of NF-κB by preventing phosphorylation and subsequent degradation of IκB-α in a prostanoid-independent manner. TNF-α-induced activation of IκB kinase was also suppressed by ASA pretreatment. These observations suggest that the anti-inflammatory effect of ASA in lung epithelial cells may be due to suppression of IκB kinase activity, which thereby inhibits subsequent phosphorylation and degradation of IκB-α, activation of NF-κB, and proinflammatory cytokine expression in lung epithelial cells.