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
01/04/2003Pubmed ID
12511556DOI
10.1074/jbc.M210559200Scopus ID
2-s2.0-0037518281 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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 AAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
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