Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38.
The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively by anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms of regulation of Cox-2 mRNA stability. Dexamethasone was found to destabilize beta-globin-Cox-2 reporter mRNAs by inhibiting p38. This inhibition occurred at the level of p38 itself: stabilization of reporter mRNA by a kinase upstream of p38 was blocked by dexamethasone, while stabilization by a kinase downstream of p38 was insensitive to dexamethasone. Inhibition of p38 activity by dexamethasone was observed in a variety of cell types treated with different activating stimuli. Furthermore, inhibition of p38 was antagonized by the anti-glucocorticoid RU486 and was delayed and actinomycin D sensitive, suggesting that ongoing glucocorticoid receptor-dependent transcription is required.
Lasa
M
M
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom.
Brook
M
M
Saklatvala
J
J
Clark
A R
AR
D020413:3' Untranslated Regions; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001483:Base Sequence; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D005914:Globins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008565:Membrane Proteins; D015735:Mifepristone / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D020413:3' Untranslated Regions; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D003609:Dactinomycin; D015735:Mifepristone; D003907:Dexamethasone; D005914:Globins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013752:Tetracycline