Selective sensitization to tumor necrosis factor-alpha-induced apoptosis by blockade of NF-kappa B in primary glomerular mesangial cells

Recent data have implicated nuclear factor kappa B (NF-kappa B) in the prev ention of apoptosis in transformed cell lines exposed to tumor necrosis fac tor alpha (TNF-alpha). However, it is obscure whether NF-kappa B plays an a nti-apoptotic role in nontransformed cells, and it is not clear whether NF- kappa B inhibits apoptosis triggered by other mediators. We investigated th e effect of specific inhibition of NF-kappa B on cytokine-induced apoptosis of glomerular mesangial cells, which is important in determining the outco me of glomerulonephritis. Cultured rat mesangial cells were stably transfec ted with the dominant negative mutant inhibitor of NF-kappa B (I kappa B al pha M), I kappa B alpha M was resistant to stimulus-dependent degradation a nd suppressed NF-kappa B activation induced by TNF-alpha (10 ng/ml) or IL-1 beta (10 ng/ml), I kappa B alpha M significantly sensitized mesangial cell s to TNF-alpha-induced apoptosis in a dose- and time-dependent manner but h ad no significant effects on the level of apoptosis in the presence of proi nflammatory or apoptosis-inducing stimuli including Fas ligand, IL-1 alpha, IL-1 beta, hydrogen peroxide, lipopolysaccharide, cycloheximide, or serum deprivation, Moreover, I kappa B alpha M-mediated sensitization to TNF-alph a overcame the protective effect of mesangial cell survival factors present in serum, which usually inhibit killing of mesangial cells by the proapopt otic stimuli used. These data show that inhibition of NF-kappa B selectivel y sensitizes primary adult glomerular mesangial cells to TNF-induced apopto sis but not to other mediators of cell death including the Fas ligand.