Suppression by Apoptotic Cells Defines Tumor Necrosis Factor-Mediated Induction of Glomerular Mesangial Cell Apoptosis by Activated Macrophages

摘要

Activated macrophages (M) isolated from inflamed glomeruli or generated by interferon- 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-/lipopolysaccharide-activated M 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 M in the presence of nitric oxide synthase inhibitors or 2) human M, both situations in which nitric oxide release was minimal. Furthermore, murine TNF knockout M were completely unable to induce mesangial cell apoptosis in the presence of nitric oxide synthase inhibitors. We conclude that TNF-restricted M-directed apoptosis of glomerular mesangial cells can be down-regulated by M binding/ingestion of apoptotic cells, suggesting a new mechanism for negative feedback regulation of M controls on resident cell number at inflamed sites.