L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes.

The L-arginine-dependent generation of reactive nitrogen intermediates (RNI) has been identified as a key intracellular antimicrobial mechanism of activated mouse macrophages. To determine the role of this mechanism in the activity of human mononuclear phagocytes, monocyte-derived macrophages activated in vitro by interferon (IFN)-gamma and monocytes from patients receiving IFN-gamma as therapy were treated with NG-monomethyl-L-arginine (NMA) or arginase. Neither competitive inhibition of L-arginine metabolism (NMA) nor depletion of L-arginine (arginase) altered intracellular antimicrobial activity against Toxoplasma gondii, Chlamydia psittaci, or Leishmania donovani. In contrast, NMA and arginase readily reversed the antimicrobial effect of mouse peritoneal macrophages stimulated either in vitro or in vivo by IFN-gamma, and activated mouse but not human cells could be induced to release enhanced levels of nitrite. These results suggest that the L-arginine-dependent generation of RNI is a species-restricted macrophage mechanism unlikely to participate in the intracellular antimicrobial activity of IFN-gamma-stimulated human mononuclear phagocytes.

Gamma interferon-activated human macrophages and Toxoplasma gondii, Chlamydia psittaci, and Leishmania donovani: antimicrobial role of limiting intracellular iron.

Iron-saturated transferrin did not reverse the intracellular killing or inhibition of Toxoplasma gondii, Chlamydia psittaci, or Leishmania donovani by gamma interferon-activated human macrophages. Deferoxamine, an iron chelator, also did not impair replication within unstimulated macrophages. Limiting the availability of intracellular iron is an unlikely mechanism in human macrophage activity against these three diverse pathogens.