Inhibition of interleukin-1-stimulated NF-kappa B RelA/p65 phosphorylationby mesalamine is accompanied by decreased transcriptional activity

Nuclear factor kappa B (NF-kappa B) is an inducible transcription factor th at regulates genes important in immunity and inflammation, The activity of NF-kappa B is highly regulated: transcriptionally active NF-kappa B protein s are sequestered in the cytoplasm by inhibitory proteins, I kappa B, A var iety of extracellular signals, including interleukin-1 (IL-1), activate NF- kappa B by inducing phosphorylation and degradation of I kappa B, allowing nuclear translocation and DNA binding of NF-kappa B. Many of the stimuli th at activate NF-kappa B by inducing I kappa B degradation also cause phospho rylation of the NF-kappa B RelA (p65) polypeptide. The transactivating capa city of RelA is positively regulated by phosphorylation, suggesting that in addition to cytosolic sequestration by I kappa B, phosphorylation represen ts another mechanism for control of NF-kappa B activity. In this report, we demonstrate that mesalamine, an anti-inflammatory aminosalicylate, dose-de pendently inhibits IL-1-stimulated NF-kappa B-dependent transcription witho ut preventing I kappa B degradation or nuclear translocation and DNA bindin g of the transcriptionally active NF-kappa B proteins, RelA, c-Rel, or RelB . Mesalamine was found to inhibit IL-1-stimulated RelA phosphorylation. The se data suggest that pharmacologic modulation of the phosphorylation status of RelA regulates the transcriptional activity of NF-kappa B, independent of nuclear translocation and DNA binding. These findings highlight the impo rtance of inducible phosphorylation of RelA. in the control of NF-kappa B a ctivity.