ANTIPARASITIC EFFECTOR MECHANISMS IN HUMAN BRAIN-TUMOR CELLS - ROLE OF INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA

Toxoplasma gondii, an obligate intracellular parasite. is able to repl icate in human brain cells. We recently showed that interferon (IFN)-g amma-activated cells from glioblastoma line 86HG39 were able to restri ct Toxoplasma growth. The effector mechanism responsible for this toxo plasmostatic effect was shown by us to be the IFN-gamma-mediated activ ation of indolamine 2.3-dioxygenase (IDO). resulting in the degradatio n of the essential amino acid tryptophan. In contrast. glioblastoma 87 HG31 was unable to restrict Toxoplasma growth after IFN-gamma activati on. and IFN-gamma-mediated IDO activation was weak. We observed that t umor necrosis factor (TNF)-alpha alone is unable to activate IDO or to induce toxoplasmostatic in any glioblastoma cell line tested. Interes tingly, we found that TNF-alpha and IFN-gamma were synergistic in the activation of IDO in glioblastoma cells 87HG31. 86HG39 and U373MG and in native astrocytes. This was shown by the measurement of enzyme acti vity as well as by the detection of IDO mRNA in TNF-alpha + IFN-gamma activated cells. This IDO activity results in a strong toxoplasmostati c effect mediated by glioblastoma cells activated simultaneously by bo th cytokines. Antibodies directed against TNF-alpha or IFN-gamma were able to inhibit IDO activity as well as the induction of toxoplasmosta sis in glioblastoma cells stimulated with both cytokines. Furthermore. it was found that the addition of L-tryptophan to the culture medium completely blocks the antiparasitic effect. We therefore conclude that both TNF-alpha and IFN-gamma may be involved in the defense against c erebral toxoplasmosis by inducing IDO activity as an antiparasitic eff ector mechanism in brain cells.