Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from L-arginine.
Recent studies show the importance of a single amino acid, L-arginine, as a necessary substrate for activated macrophage-mediated cytotoxic activity for tumor target cells and microbiostatic function for Cryptococcus neoformans. The present studies were carried out to determine the role of the L-arginine-dependent macrophage effector function on the microbiostatic effects of activated macrophages on the obligate intracellular protozoan, Toxoplasma gondii. A guanidino methylated derivative of L-arginine, NGmonomethyl-L-arginine (NGMMA), a competitive inhibitor of the L-arginine-dependent effector pathway, virtually abolished the normally potent microbiostatic effect of macrophages for Toxoplasma gondii after activation of the macrophages in vitro by IFN-gamma and LPS or in vivo by i.p. injection of killed Corynebacterium parvum. Addition of supplemental L-arginine to the culture medium overcame the capacity of NGMMA to block activated macrophage-mediated microbiostasis of Toxoplasma. The ability of NGMMA to inhibit the microbiostatic capacity of activated macrophages for Toxoplasma gondii correlated with almost total inhibition of synthesis of nitrite, nitrate, and L-citrulline from L-arginine. Therefore, as is the case for tumor target cells and C. neoformans, the synthesis of inorganic nitrogen oxides from a terminal guanidino nitrogen atom of L-arginine appears to be essential for murine cytotoxic activated macrophage mediated microbiostatic capacity for T. gondii.
Adams
L B
LB
Immunology Research Department, Gillis W. Long Hansen's Disease Center, Carville, LA 70721.
Hibbs
J B
JB
Taintor
R R
RR
Krahenbuhl
J L
JL
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002956:Citrulline / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009589:Nitrogen Oxides / Q000633:toxicity*; D014122:Toxoplasma / Q000276:immunology*; D019323:omega-N-Methylarginine
D009566:Nitrates; D009573:Nitrites; D009589:Nitrogen Oxides; D019323:omega-N-Methylarginine; D002956:Citrulline; D001120:Arginine