Production of nitric oxide (NO) is not essential for protection against acute Toxoplasma gondii infection in IRF-1-/- mice.
Production of nitric oxide (NO) by macrophages is important for the killing of intracellular pathogens. IFN-gamma and LPS stimulate NO production by transcriptional up-regulation of inducible nitric oxide synthetase (iNOS). In the present study we used mice with a targeted disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to investigate the importance of NO in the host immune response against Toxoplasma gondii, a major cause of infection in newborns and those with AIDS. IRF-1-/- mice were more susceptible to acute Toxoplasma infection, and treatment with either exogenous IFN-gamma or in vivo neutralization of endogenous IFN-gamma had little effect on their susceptibility to infection. However, administration of exogenous IL-12 was able to prolong survival even when IFN-gamma was depleted. An in vivo depletion study suggested that the mechanism of this protective response is mediated in part by CD4+ T cells. The administration of IL-12 could not overcome the inhibition of lymphoproliferative response in T. gondii-infected mice and treatment with N-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase (iNOS) antagonist in vitro was unable to reverse the immunosuppression. In response to Toxoplasma infection, splenocytes from IRF-1-/- mice exhibited increased production of IL-10 as well as a 30-fold increase in its message expression. These studies indicate that NO may not be essential for host immunity to the parasite, and moreover that IL-12 appears to induce an IFN-gamma-independent mechanism of protection against this opportunistic pathogen.
Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
I A
IA
Khan
T
T
Matsuura
S
S
Fonseka
L H
LH
Kasper
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D007155:Immunologic Factors / Q000627:therapeutic use; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D014122:Toxoplasma / Q000502:physiology*; D014124:Toxoplasmosis, Animal / Q000517:prevention & control* / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019323:omega-N-Methylarginine
D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase