title: Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells.
abstract: Renal mesangial cell apoptosis is a crucial repair mechanism in glomerular nephritis (GN). These cells express receptors to tumor necrosis factor alpha (TNFalpha), a cytokine with proapoptotic properties implicated in the resolution of GN. Progression to proliferative GN is accompanied by cyclooxygenase-mediated formation of prostaglandins and inefficient apoptosis of mesangial cells. The aims of this study were to quantify TNFalpha-mediated apoptosis in renal mesangial cells and to determine whether expression of the inducible form of cyclooxygenase, cylooxygenase-2 (COX-2), inhibits this apoptosis. By 24 h significant levels of apoptosis were induced by TNFalpha (100 ng/ml) or etoposide control (100 microm), as shown by phosphatidylserine externalization, caspase-3 activation, development of a sub-G(0)/G(1) region, and distinct chromatin condensation. Using adenoviral-mediated delivery of the COX-2 gene (AdCOX-2) apoptotic features were prevented from appearing in AdCOX-2 cells treated with TNFalpha, whereas etoposide-treated AdCOX-2 cells were not protected. Furthermore, COX-2 expression, induced by the vasoconstrictor peptide ET-1 or the cytokine interleukin-1beta also inhibited TNFalpha-mediated but not etoposide-mediated apoptosis, to an extent, similar to adenoviral COX-2 infection. Selective COX-2 inhibition by NS-398 restored TNFalpha-mediated apoptosis. Prostaglandin (PG) E(2) and PGI(2) were shown to be the major prostaglandin metabolites in AdCOX-2 cells. The addition of PGE(2) and PGI(2) protected against TNFalpha-mediated apoptosis. These results demonstrate COX-2 anti-apoptotic activity via a death receptor route and suggest that selective COX-2 inhibition may augment TNFalpha apoptosis in chronic inflammatory conditions.
authors.affiliation: Department of Medicine and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: Adiba
authors.initials: A
authors.lastname: Ishaque
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dunn
authors.forename: Andrey
authors.initials: A
authors.lastname: Sorokin
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D061945:Caspase Inhibitors; D019332:Endothelin-1; D007375:Interleukin-1; D007527:Isoenzymes; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C505410:Casp3 protein, rat; D053148:Caspase 3; D015232:Dinoprostone