Activated macrophages direct apoptosis and suppress mitosis of mesangial cells

J S Duffield, L P Erwig, X Q Wei, F Y Liew, A J Rees, J S Savill

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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. The Journal of Immunology, 2000, 164: 2110-2119.

Original languageEnglish
Pages (from-to)2110-2119
Number of pages10
JournalThe Journal of Immunology
Volume164
Publication statusPublished - 2000

Keywords

  • NITRIC-OXIDE SYNTHASE
  • MRL-LPR/LPR MICE
  • HUMAN GLOMERULONEPHRITIS
  • INDUCE APOPTOSIS
  • AUTOIMMUNE-DISEASE
  • MESSENGER-RNA
  • L-ARGININE
  • EXPRESSION
  • RAT
  • RECEPTOR

Cite this

Duffield, J. S., Erwig, L. P., Wei, X. Q., Liew, F. Y., Rees, A. J., & Savill, J. S. (2000). Activated macrophages direct apoptosis and suppress mitosis of mesangial cells. The Journal of Immunology, 164, 2110-2119.