Activated macrophages direct apoptosis and suppress mitosis of mesangial cells

During inflammation in the glomerulus, the complement of resident myofibrob last-like mesangial cells is regulated by mitosis and apoptosis, but the ce llular mechanisms controlling the size of mesangial cell populations have r emained obscure. Prompted by studies of development, we sought evidence tha t macrophages regulate mesangial cell number. Rat bone marrow-derived macro phages primed with IFN-gamma then further activated in coculture with LPS o r TNF-alpha elicited a 10-fold induction of rat mesangial cell apoptosis an d complete suppression of mitosis, effects inhibitable by the NO synthase i nhibitors L-monomethyl arginine and L-N-6-(1-iminoethyl) lysine dihydrochlo ride, Complete dependence upon macrophage-derived NO was observed in compar able experiments employing activated bone marrow macrophages from wild-type and NO synthase 2(-/-) mice. Nevertheless, when mesangial cells were prime d with IFN-gamma plus TNF-alpha, increased induction by activated macrophag es of mesangial apoptosis exhibited a NO-independent element. The use of gl d/gld macrophages excluded a role for Fas ligand in this residual kill, des pite increased expression of Fas and increased susceptibility to soluble Fa s ligand exhibited by cytokine primed mesangial cells. Finally, activated m acrophages isolated from the glomeruli of rats with nephrotoxic nephritis a lso induced apoptosis and suppressed mitosis in mesangial cells by an L-mon omethyl arginine-inhibitable mechanism. These data demonstrate that activat ed macrophages, via the release of NO and other mediators, regulate mesangi al cell populations in vitro and may therefore control the mesangial cell c omplement at inflamed sites. The Journal of Immunology, 2000, 164: 2110-211 9.