Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells

J Biol Chem. 2003 Mar 21;278(12):10629-40. doi: 10.1074/jbc.M210559200. Epub 2003 Jan 1.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspase Inhibitors
  • Cells, Cultured
  • Cyclooxygenase 2
  • Dinoprostone / pharmacology
  • Endothelin-1 / pharmacology
  • Epoprostenol / pharmacology
  • Etoposide / pharmacology
  • Glomerular Mesangium / cytology*
  • Interleukin-1 / pharmacology
  • Isoenzymes / physiology*
  • Male
  • Prostaglandin-Endoperoxide Synthases / physiology*
  • Prostaglandins / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

  • Caspase Inhibitors
  • Endothelin-1
  • Interleukin-1
  • Isoenzymes
  • Prostaglandins
  • Tumor Necrosis Factor-alpha
  • Etoposide
  • Epoprostenol
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Casp3 protein, rat
  • Caspase 3
  • Dinoprostone