title: Activated macrophages direct apoptosis and suppress mitosis of mesangial cells.
abstract: During inflammation in the glomerulus, the complement of resident myofibroblast-like mesangial cells is regulated by mitosis and apoptosis, but the cellular mechanisms controlling the size of mesangial cell populations have remained obscure. Prompted by studies of development, we sought evidence that macrophages regulate mesangial cell number. Rat bone marrow-derived macrophages primed with IFN-gamma then further activated in coculture with LPS or TNF-alpha elicited a 10-fold induction of rat mesangial cell apoptosis and complete suppression of mitosis, effects inhibitable by the NO synthase inhibitors L-monomethyl arginine and L-N(6)-(1-iminoethyl) lysine dihydrochloride. Complete dependence upon macrophage-derived NO was observed in comparable experiments employing activated bone marrow macrophages from wild-type and NO synthase 2(-/-) mice. Nevertheless, when mesangial cells were primed with IFN-gamma plus TNF-alpha, increased induction by activated macrophages of mesangial apoptosis exhibited a NO-independent element. The use of gld/gld macrophages excluded a role for Fas ligand in this residual kill, despite increased expression of Fas and increased susceptibility to soluble Fas ligand exhibited by cytokine-primed mesangial cells. Finally, activated macrophages isolated from the glomeruli of rats with nephrotoxic nephritis also induced apoptosis and suppressed mitosis in mesangial cells by an L-monomethyl arginine-inhibitable mechanism. These data demonstrate that activated macrophages, via the release of NO and other mediators, regulate mesangial cell populations in vitro and may therefore control the mesangial cell complement at inflamed sites.
authors.affiliation: Centre for Inflammation Research, Department of Clinical Sciences, Royal Infirmary, University of Edinburgh, Edinburgh, United Kingdom. j.duffield@ed.ac.uk
authors.forename: J S
authors.initials: JS
authors.lastname: Duffield
authors.forename: L P
authors.initials: LP
authors.lastname: Erwig
authors.forename: X
authors.initials: X
authors.lastname: Wei
authors.forename: F Y
authors.initials: FY
authors.lastname: Liew
authors.forename: A J
authors.initials: AJ
authors.lastname: Rees
authors.forename: J S
authors.initials: JS
authors.lastname: Savill
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D005920:Glomerular Mesangium / Q000166:cytology* / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology; D007399:Interphase / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000276:immunology*; D009393:Nephritis / Q000276:immunology / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008024:Ligands; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat