Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 327, Issue 1-2, Pages 101-110Publisher
SPRINGER
DOI: 10.1007/s11010-009-0048-y
Keywords
Cyclooxygenase-2; Diclofenac; J774.2; Lipopolysaccharide; Paracetamol; Peroxisome proliferator-activated receptor-gamma
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Funding
- Biotechnological and Biological Sciences Research Council (BBSRC)
- GlaxoSmithKline (GSK)
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Cyclooxygenase-2 (COX-2) is an inducible isoform of the COX family of enzymes central to the synthesis of pro-inflammatory prostaglandins. Induction of COX-2 is mediated by many endogenous and exogenous molecules that include pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS). It has been demonstrated that COX-2 can also be induced by diclofenac in cultured J774.2 macrophages. This induction was delayed compared to COX-2 induced by LPS and paracetamol selectively inhibited activity of this protein. The aim of the present study was to determine the transcription factor involved in the production of COX-2 after treatment of J774.2 cells with 500 mu M diclofenac. Pre-treatment of cells with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) antagonists GW9662 (0.1-1 mu M) or biphenol A Diglycidyl Ether (100-200 mu M) resulted in reduction of the induction of COX-2 by diclofenac, but not by LPS. Induction of COX-2 by the PPAR-gamma agonist 15deoxy Delta(12,14)prostaglandin J(2) was also reduced when the cells were pre-treated with the PPAR-gamma antagonists BADGE or GW9662. On the other hand, pre-treatment of cells with the nuclear factor-kappa-B (NF-kappa B) Super-repressor I kappa B alpha (150-600 nM) reduced the induction of COX-2 by LPS, but not by diclofenac. We, therefore, have identified that PPAR-gamma activation is a requirement for COX-2 induction after diclofenac stimulation of J774.2 cells. These results along with the finding that treatment of J774.2 macrophages with diclofenac resulted in the release of the anti-inflammatory cytokines, interleukin-10 and transforming growth factor-beta suggest that the diclofenac-induced COX-2 protein may possess anti-inflammatory actions.
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