Inducible anti-parasitic effector mechanisms in human uroepithelial cells:tryptophan degradation vs. NO production

In murine cells the most important effector mechanism directed against the intracellular pathogen Toxoplasma gondii is the production of toxic nitroge n oxides. In contrast the induction of the tryptophan degrading enzyme indo lamine 2,3-dioxygenase (IDO) has been described to be the most effective an ti-parasitic mechanism in most human cells. In this report we analysed IDO induction and NO production in the human uroepithelial carcinoma cell line RT4. We found that after stimulation with IFN-gamma these cells were able t o restrict toxoplasma growth. This was due to an activation of IDO, and the anti-parasitic effect mediated by RT4 cells was abrogated by the addition of L-tryptophan. In addition we found that the costimulation of RT4 cells w ith IL-1 and IFN-gamma results in the production of nitric oxide, and that in RT4 cells stimulated with both these cytokines, IDO activity and toxopla smostasis was lower than in cells stimulated with IFN-gamma alone. This IL- 1-mediated inhibition of IFN-gamma-induced IDO activity and toxoplasmostasi s could be blocked by monomethyl L-arginine, an inhibitor of NO production. We therefore conclude that the induction of indolamine 2,3-dioxygenase act ivity in human cells is a very important effector mechanism directed agains t Toxoplasma gondii, and that in human cells the production of NO might be involved in the regulation of IDO activity.