TUMOUR NECROSIS FACTOR-α-DEPENDENT REGULATION OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2

Abstract

Tumour necrosis factor α (TNF-α)-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-α-induced PGE2production was evident after 12 h and was associated with a significant TNF-α-mediated increase in PGHS-2 immunoreactive protein. A specific PGHS-2 inhibitor, NS-398, completely abolished the TNF-α-mediated increase in PGE2production, suggesting that the PGE2formed in response to TNF-α was derived from PGHS-2. TNF-α-mediated PGHS-2 mRNA accumulation was observed at 1 h, remained elevated foo 24 h, and was blocked by actinomycin D, indicating that TNF-α 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-α-stimulated cells. Inhibition of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) inhibited the TNF-α-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-α.