A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA.
The mechanism by which p38 mitogen-activated protein kinase (MAPK) regulates the induction of cyclooxygenase (COX)-2 by interleukin-1 (IL-1) has been investigated in HeLa cells. SB 203580, an inhibitor of p38 MAPK, in the range 0.1-1 microM inhibited IL-1-stimulated PGE2 (but not arachidonic acid) release and this was associated with inhibition of induction of COX-2 protein and mRNA. IL-1 stimulated COX-2 transcription in HeLa cells about 2-fold as judged by both reporter gene and nuclear run-on assays. The inhibitor had no significant effect on this. However, in cells previously stimulated with IL-1 it caused rapid destabilisation of COX-2 mRNA independently of on-going transcription. The results suggest a novel function for p38 MAPK in the regulation of mRNA stability.
Ridley
S H
SH
Kennedy Institute of Rheumatology, London, UK.
Dean
J L
JL
Sarsfield
S J
SJ
Brook
M
M
Clark
A R
AR
Saklatvala
J
J
D001095:Arachidonic Acids / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580