A PPAR-independent pathway to PUFA-induced COX-2 expression.
Polyunsaturated fatty acids (PUFAs) induce COX-2 in bovine endometrial stromal cells through activation of peroxisome-proliferator-activated receptor alpha (PPARalpha). We have investigated alternative (PPAR-independent) pathways to COX-2 induction using a reporter construct driven by a COX-2 gene promoter sequence lacking a PPAR response element. This construct was induced by PUFAs, but not by PPAR agonists. PPAR-independent reporter gene expression occurred 6h after PPAR-dependent induction of the endogenous COX-2 gene. In contrast to PPAR-dependent COX-2 induction, which is not affected by NF-kappaB inhibitors, the PPAR-independent pathway was blocked by the NF-kappaB inhibitor MG132 or following deletion of NF-kappaB sites in the COX-2 promoter. The PPAR-independent effect of PUFA was mimicked by the PKC activators 4beta-PMA and prostaglandin F(2alpha), but was not blocked by the PKC inhibitor RO318425. The results demonstrate a pathway to the induction of COX-2 by PUFAs requiring NF-kappaB but not PPAR or PKC.
Derecka
K
K
Division of Animal Physiology, University of Nottingham, Sutton Bonington Campus, Loughborough, Leics LE12 5RD, UK.
Sheldrick
E L
EL
Wathes
D C
DC
Abayasekara
D R E
DR
Flint
A P F
AP
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D014162:Transfection
D005231:Fatty Acids, Unsaturated; D016328:NF-kappa B; D047492:Peroxisome Proliferator-Activated Receptors; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C