Nitric oxide synthase induces macrophage death by apoptosis

Biochem Biophys Res Commun. 1993 Mar 15;191(2):503-8. doi: 10.1006/bbrc.1993.1246.


Stimulation processes effective for macrophage (M phi) cytostasis induction also led to a L-arginine-dependent M phi cell death by apoptosis in parallel to nitrite and citrulline production. Resident M phi stimulated with LPS plus IFN-gamma and MDP produced high amounts of nitrite and underwent apoptosis. Inflammatory M phi treated with LPS or IFN-gamma alone produced low levels of nitrite and were not apoptotic, whereas a synergistic effect was observed, the combined treatment leading to high amounts of nitrite and to apoptosis. Primed M phi obtained from concanavalin A-treated mice, after stimulation with LPS alone, released high amounts of nitrite and exhibited the typical ladder pattern of DNA fragmentation of apoptotic cells. In the three cases the L-arginine-dependent nitrite production was inhibited by NG-monomethyl-L-arginine, a competitive inhibitor of NO synthase, which moreover, also inhibited cell apoptosis. These findings and kinetics studies suggest the involvement of NO synthase in apoptosis induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / physiology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cells, Cultured
  • Citrulline / biosynthesis
  • Female
  • Macrophage Activation
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C3H
  • Nitric Oxide Synthase
  • Nitrites / metabolism


  • Nitrites
  • Citrulline
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases