Inhibition of Interleukin-1-stimulated NF-κB RelA/p65 Phosphorylation by Mesalamine Is Accompanied by Decreased Transcriptional Activity
| Autor: | David J. McKean, James J. Lipsky, William J. Sandborn, Laurence J. Egan, Dennis C. Mays, M G Pike, Michael P. Bell, Cathy Huntoon |
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| Rok vydání: | 1999 |
| Předmět: |
Transcription
Genetic Biology Biochemistry Aminosalicylate Ligases chemistry.chemical_compound Transcription (biology) Humans Phosphorylation Mesalamine Molecular Biology Transcription factor DNA Primers Cell Nucleus RELA Base Sequence RELB NF-kappa B Biological Transport NF-κB Cell Biology Molecular biology Cytosol chemistry Caco-2 Cells Interleukin-1 |
| Zdroj: | Journal of Biological Chemistry. 274:26448-26453 |
| ISSN: | 0021-9258 |
| Popis: | Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that regulates genes important in immunity and inflammation. The activity of NF-kappaB is highly regulated: transcriptionally active NF-kappaB proteins are sequestered in the cytoplasm by inhibitory proteins, IkappaB. A variety of extracellular signals, including interleukin-1 (IL-1), activate NF-kappaB by inducing phosphorylation and degradation of IkappaB, allowing nuclear translocation and DNA binding of NF-kappaB. Many of the stimuli that activate NF-kappaB by inducing IkappaB degradation also cause phosphorylation of the NF-kappaB RelA (p65) polypeptide. The transactivating capacity of RelA is positively regulated by phosphorylation, suggesting that in addition to cytosolic sequestration by IkappaB, phosphorylation represents another mechanism for control of NF-kappaB activity. In this report, we demonstrate that mesalamine, an anti-inflammatory aminosalicylate, dose-dependently inhibits IL-1-stimulated NF-kappaB-dependent transcription without preventing IkappaB degradation or nuclear translocation and DNA binding of the transcriptionally active NF-kappaB proteins, RelA, c-Rel, or RelB. Mesalamine was found to inhibit IL-1-stimulated RelA phosphorylation. These data suggest that pharmacologic modulation of the phosphorylation status of RelA regulates the transcriptional activity of NF-kappaB, independent of nuclear translocation and DNA binding. These findings highlight the importance of inducible phosphorylation of RelA in the control of NF-kappaB activity. |
| Databáze: | OpenAIRE |
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