Activated macrophages (Mπ) isolated from inflamed glomeruli or generated by interferon-γ and lipopolysaccharide treatment in vitro induce glomerular mesangial cell apoptosis by hitherto incompletely understood mechanisms. In this report we demonstrate that nitric oxide-independent killing of co-cultured mesangial cells by interferon-γ/lipopolysaccharide-activated Mπ is suppressed by binding/ingestion of apoptotic cells and is mediated by tumor necrosis factor (TNF). Thus, soluble TNF receptor-1 significantly inhibited induction of mesangial cell apoptosis by 1) rodent Mπ in the presence of nitric oxide synthase inhibitors or 2) human Mπ, both situations in which nitric oxide release was minimal. Furthermore, murine TNF knockout Mπ were completely unable to induce mesangial cell apoptosis in the presence of nitric oxide synthase inhibitors. We conclude that TNF-restricted Mπ-directed apoptosis of glomerular mesangial cells can be down-regulated by Mπ binding/ingestion of apoptotic cells, suggesting a new mechanism for negative feedback regulation of Mπ controls on resident cell number at inflamed sites.