Suppression by apoptotic cells defines tumor necrosis factor-mediated induction of glomerular mesangial cell apoptosis by activated macrophages

Activated macrophages (M phi) isolated from inflamed glomeruli or generated by interferon-gamma and lipopolysaccharide treatment in vitro induce glome rular mesangial cell apoptosis by hitherto incompletely understood mechanis ms. in this report we demonstrate that nitric oxide-independent killing of co-cultured mesangial cells by interferon-gamma /lipopolysaccharide-activat ed M phi is suppressed by binding/ingestion of apoptotic cells and is media ted by rumor necrosis factor (TNF). Thus, soluble TNF receptor-1 significan tly inhibited induction of mesangial cell apoptosis by 1) rodent M phi in t he presence of nitric oxide synthase inhibitors or 2) human M phi both situ ations in which nitric oxide release was minimal. Furthermore, murine TNF k nockout M phi were completely unable to induce mesangial cell apoptosis in the presence of nitric oxide synthase inhibitors. We conclude that TNF-rest ricted M phi -directed apoptosis of glomerular mesangial cells can be down- regulated by M phi binding/ingestion of apoptotic cells, suggesting a new m echanism for negative feedback regulation of M phi controls on resident cel l number at inflamed sites.