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(American Journal of Pathology. 2001;159:1397-1404.)
© 2001 American Society for Investigative Pathology

Regular Articles

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

Jeremy S. Duffield^*, Carl F. Ware, Bernhardt Ryffel and John Savill^*

From the Medical Research Council Centre for Inflammation Research,^*
University of Edinburgh, Edinburgh, United Kingdom; the La Jolla Institute for Allergy and Immunology,
University of California, San Diego, California; and the Department of Medicine,
University of Cape Town, Cape Town, South Africa

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.

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