Feedback control of cyclooxygenase-2 expression through PPARgamma

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Cyclooxygenase-2 (COX-2) is vital for prostaglandin synthesis, impacting inflammation, cancer, and cardiovascular health.
• 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2)), a PGD(2) metabolite, is a potent ligand for peroxisome proliferator-activated receptor-gamma (PPARgamma).
• PPARgamma in macrophages is linked to inflammation regulation and foam cell differentiation in atherogenesis.

Purpose of the Study:

• To investigate the role of 15d-PGJ(2) and PPARgamma in regulating lipopolysaccharide (LPS)-induced COX-2 expression in macrophages versus vascular endothelial cells.
• To elucidate the signaling pathways involved in COX-2 regulation by 15d-PGJ(2) and dexamethasone (DEX).

Main Methods:

• Utilized U937 macrophage-like cells and vascular endothelial cells.
• Assessed COX-2 expression and promoter activity following LPS stimulation.
• Investigated the role of PPARgamma and glucocorticoid receptor (GR) signaling pathways.
• Employed gene transfection to introduce PPARgamma into endothelial cells.

Main Results:

• 15d-PGJ(2) suppressed LPS-induced COX-2 expression in U937 cells, but not endothelial cells.
• LPS downregulated PPARgamma mRNA in U937 cells while upregulating GR mRNA.
• Both 15d-PGJ(2) and DEX inhibited COX-2 promoter activity via NF-kappaB pathway interference.
• Transfecting endothelial cells with PPARgamma conferred 15d-PGJ(2)-mediated COX-2 suppression.

Conclusions:

• COX-2 expression is regulated by a PPARgamma-mediated negative feedback loop, particularly in macrophages.
• This feedback mechanism allows dynamic prostaglandin production, influencing COX-2's diverse roles.
• The findings highlight cell-specific regulation of COX-2 by PPARgamma and its implications in inflammatory processes.