IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism.
Primary cultures of BALB/cJ hepatocytes treated with 10(3) U/ml rIFN-gamma consistently inhibited intracellular Plasmodium berghei liver schizont development by 50 to 70%. Monomethyl-L-arginine (NGMMLA), the competitive inhibitor of L-arginine as substrate for production of nitric oxides by hepatocytes, reversed the activity of IFN-gamma on these malaria-infected cells. Reversal of IFN-gamma activity by NGMMLA was dose dependent and was maximal at 0.5 mM NGMMLA. Depletion of L-arginine by addition of arginase to the culture medium blocked the capacity of IFN-gamma to inhibit parasite development in hepatocytes; addition of excess L-arginine to cultures treated with IFN-gamma in the presence of NGMMLA competitively restored IFN-gamma capacity to activate hepatocyte anti-parasite activity. TNF-alpha was neither required for IFN-gamma activity, nor effective at any concentration tested as an inhibitor of schizont development by itself in primary hepatocytes. These data strongly suggest that the action of IFN-gamma on P. berghei-infected hepatocytes is to induce the production of L-arginine-derived nitrogen oxides that are toxic for the intracellular parasite.
Mellouk
S
S
Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889-5055.
Green
S J
SJ
Nacy
C A
CA
Hoffman
S L
SL
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000494:pharmacology*; D008099:Liver / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009589:Nitrogen Oxides / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019323:omega-N-Methylarginine
D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D001120:Arginine