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

Mol Cell Biol. 1998 Jan;18(1):78-84. doi: 10.1128/MCB.18.1.78.

Abstract

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-kappaB. Activation of NF-kappaB by TNF and IL-1 is initiated by the phosphorylation of the inhibitory subunit, IkappaB, which targets IkappaB for degradation and leads to the release of active NF-kappaB. The nonsteroidal anti-inflammatory drug sodium salicylate (NaSal) interferes with TNF-induced NF-kappaB activation by inhibiting phosphorylation and subsequent degradation of the IkappaB alpha protein. Recent evidence indicated that NaSal activates the p38 mitogen-activated protein kinase (MAPK), raising the possibility that inhibition of NF-kappaB activation by NaSal is mediated by p38 MAPK. We now show that inhibition of TNF-induced IkappaB 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 IkappaB alpha degradation were seen after only 30 s to 1 min of NaSal treatment. Induction of p38 MAPK activation and inhibition of TNF-induced IkappaB alpha degradation were demonstrated with pharmacologically achievable doses of NaSal. These findings provide evidence for a role of NaSal-induced p38 MAPK 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-kappaB activation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • DNA-Binding Proteins / metabolism*
  • I-kappa B Proteins*
  • Mitogen-Activated Protein Kinases*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • Phosphorylation
  • Signal Transduction / drug effects*
  • Sodium Salicylate / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Sodium Salicylate