Faculty Collaboration Database

Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells. J Biol Chem 2003 Mar 21;278(12):10629-40

Date

01/04/2003

Pubmed ID

12511556

DOI

10.1074/jbc.M210559200

Scopus ID

2-s2.0-0037518281 (requires institutional sign-in at Scopus site)   36 Citations

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.

Author List

Ishaque A, Dunn MJ, Sorokin A

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Caspase 3
Caspase Inhibitors
Cells, Cultured
Cyclooxygenase 2
Dinoprostone
Endothelin-1
Epoprostenol
Etoposide
Glomerular Mesangium
Interleukin-1
Isoenzymes
Male
Prostaglandin-Endoperoxide Synthases
Prostaglandins
Rats
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha