Anti‐parasitic effector mechanisms in human brain tumor cells: Role of interferon‐γ and tumor necrosis factor‐α

Abstract

Toxoplasma gondii, an obligate intracellular parasite, is able to replicate in human brain cells. We recently showed that interferon (IFN)-gamma-activated cells from glioblastoma line 86HG39 were able to restrict Toxoplasma growth. The effector mechanism responsible for this toxoplasmostatic effect was shown by us to be the IFN-gamma-mediated activation of indolamine 2,3-dioxygenase (IDO), resulting in the degradation of the essential amino acid tryptophan. In contrast, glioblastoma 87HG31 was unable to restrict Toxoplasma growth after IFN-gamma activation, and IFN-gamma-mediated IDO activation was weak. We observed that tumor necrosis factor (TNF)-alpha alone is unable to activate IDO or to induce toxoplasmostasis in any glioblastoma cell line tested. Interestingly, 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 activity as well as by the detection of IDO mRNA in TNF-alpha + IFN-gamma activated cells. This IDO activity results in a strong toxoplasmostatic effect mediated by glioblastoma cells activated simultaneously by both cytokines. Antibodies directed against TNF-alpha or IFN-gamma were able to inhibit IDO activity as well as the induction of toxoplasmostasis 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 cerebral toxoplasmosis by inducing IDO activity as an antiparasitic effector mechanism in brain cells.

Indoleamine 2,3-Dioxygenase Mediates Cell Type-Specific Anti-Measles Virus Activity of Gamma Interferon

“…However, in the same cells, IDO is active against bacteria. Furthermore, IDO has been found to mediate antiparasitic activities in human fibroblasts, endothelial cells, and glioblastomas (1,14,31). It was observed earlier that IFN-␥ induces IDO only in certain primary cells or cell lines (57).…”

CD40 Induces Anti-Toxoplasma gondii Activity in Nonhematopoietic Cells Dependent on Autophagy Proteins

“…Incubation of immortalized human microvascular brain endothelial cells with IFN-␥ causes toxoplasmastatic activity that is mediated by upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO) (72), an enzyme that starves the parasite of tryptophan and was previously shown to mediate toxoplasmastasis induced by IFN-␥ in human fibroblasts (73). IFN-␥ also utilizes IDO upregulation to inhibit the growth of the parasite within astrocytoma cells without reducing the number of infected cells (74,75). In contrast, IFN-␥ induces anti-T. gondii activity in primary mouse astrocytes by recruiting the p47 GTPase IGTP to the parasitophorous vacuole and causing vacuolar disruption (76).…”

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

“…Cell surface TNF has been shown to mediate cytotoxic activities by CD4 ϩ T cells, as measured via L929 fibroblast lysis assays (25) and thus can act via mechanisms other than up-regulation of NO. Furthermore, TNF in combination with IFN-␥ can synergistically activate a diverse number of other macrophage antimicrobial activities, such as expression of the tryptophan-limiting enzyme indolamine 2, 3-oxygenase (26,27), or induction of apoptosis (28). The combined action of these two cytokines may also redirect the intracellular trafficking of LVS to a compartment that does not support replication of the organism.…”