Tumour necrosis factor-alpha-dependent regulation of prostaglandin endoperoxide synthase-2.
Tumour necrosis factor alpha (TNF-alpha)-mediated regulation of prostaglandin endoperoxide synthase-2 (PGHS-2) mRNA levels was examined in murine fibrosarcoma MCA-101 cells. We demonstrated that the formation of prostaglandin E2 (PGE2) is highly dependent on the expression of PGHS-2 enzyme in these cells. TNF-alpha-induced PGE2 production was evident after 12 h and was associated with a significant TNF-alpha-mediated increase in PGHS-2 immunoreactive protein. A specific PGHS-2 inhibitor, NS-398, completely abolished the TNF-alpha-mediated increase in PGE2 production, suggesting that the PGE2 formed in response to TNF-alpha was derived from PGHS-2. TNF-alpha-mediated PGHS-2 mRNA accumulation was observed at 1 h, remained elevated for 24 h, and was blocked by actinomycin D, indicating that TNF-alpha increases PGHS-2 gene transcription. A significant post-transcriptional mechanism also contributed to the increased PGHS-2 mRNA accumulation as the mRNA half-life was approximately 4-5 h in TNF-alpha-stimulated cells. Inhibition of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) inhibited the TNF-alpha-mediated increase in PGHS-2 mRNA levels. We suggest that PTPs and PTKs play a role in the transcriptional and/or post-transcriptional mechanisms that contribute to the regulation of the PGHS-2 gene by TNF-alpha.
Mahboubi
K
K
Department of Pharmacology, New York Medical College, Valhalla, USA.
Young
W
W
Ferreri
N R
NR
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D019833:Genistein / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D001152:Arsenicals; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C029341:oxophenylarsine; D019833:Genistein; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D015232:Dinoprostone