Human Indoleamine 2,3-Dioxygenase InhibitsToxoplasma gondiiGrowth in Fibroblast Cells

Abstract

Interferon-gamma (IFN-gamma) is known to inhibit the growth of Toxoplasma gondii both in vivo and in vitro. The IFN-gamma induced anti-toxoplasma activity in human cells is strongly correlated with the degradation of the essential amino acid L-tryptophan in vitro. Destruction of L-tryptophan is due to an increased activity of indoleamine 2,3-dioxygenase (IDO), which is transcriptionally activated by IFN-gamma. To determine if indoleamine 2,3-dioxygenase alone is sufficient to block the T. gondii growth, we transfected human fibroblast cells with an IDO cDNA expression plasmid using a metallothionein-inducible promoter. We showed that IDO mRNA and its enzymatic activity are inducible in fibroblast cells transfected with right-orientation IDO cDNA upon addition of CdCl2 to culture medium. The elevated IDO enzyme activity is strongly correlated with an inhibition of T. gondii growth. No IDO mRNA nor enzyme activity is induced by CdCl2 in reverse orientation transfected cells, and no adverse effects were observed on T. gondii growth in cells transfected with the reverse IDO-construct or in control parent cells with or without supplementation of CdCl2. Our observations along with the recent report by Habara-Ohkubo et al. (Infect. Immun. 61, 1810-1813, 1993) suggest that IFN-gamma-induced antitoxoplasma activity is due at least in part to the activation of IDO gene.