Activation of p38 mitogen-activated protein kinase by sodium salicylate leads to inhibition of tumor necrosis factor-induced IκBα phosphorylation and degradation

Many actions of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) on gene expression are mediated by the transcription factor NF-KB. Activation of NF-KB by TNF and IL-I is initiated by the phosphorylation of the inhibitory subunit, I kappa B, which targets I kappa B for degradation and leads to the release of active NF-kappa B, The nonsteroidal anti-inflammatory drug sodium salicylate (NaSal) interferes with TNF-induced NF-KB activation by inhibiting phosphorylation and subsequent degradation of the I kappa B alpha protein, Recent evidence indicated that NaSal activates the p38 mitogen-activated protein kinase (MAPK), raising the possibility that inhibition of NF-kappa B activation by Nasal is mediated by p38 MAPK. We now show that inhibition of TNF-induced I kappa B alpha phosphorylation and degradation by Nasal is prevented by treatment of cells with SB203580, a highly specific p38 MAPK inhibitor, Both p38 activation and inhibition of TNF-induced I kappa B alpha degradation were seen after only 30 s to 1 min of NaSal treatment, Induction of p38 MAPK activation and inhibition of TNF-induced I kappa B alpha degradation were demonstrated with pharmacologically achievable doses of Nasal, These findings provide evidence for a role of Nasal-induced p38 MARK activation in the inhibition of TNF signaling and suggest a possible role for the p38 MAPK in the anti-inflammatory actions of salicylates. In addition, these results implicate the p38 MAPK as a possible negative regulator of TNF signaling that leads to NF-kappa B activation.