IL-4 and IL-13 regulate the induction of indoleamine 2,3-dioxygenase activity and the control of Toxoplasma gondii replication in human fibroblasts activated with IFN-γ

Abstract

The ability of up-regulatory [recombinant (r) IFN-γ, rIFN-β and rTNF-α] and down-regulatory (rIL-4, rIL-10 and rIL-13) cytokines to control the expression of indoleamine 2,3-dioxygenase (INDO) and anti-Toxoplasma activity in the human fibrosarcoma cell line 2C4 was evaluated. Activation of fibroblasts with rIFN-γ, rIFN-β and rIFN-α resulted in augmentation of INDO expression and activity leading to 40.0, 25.0 and 27.0% inhibition of tachyzoite growth, respectively. An additive effect was observed when host cells were incubated with rIFN-γ plus rTNF-α. With regard to the down-regulatory cytokines we observed that IL-4 as well as IL-13, but not IL-10, induced significant inhibition of IFN-γ-induced control of parasite replication, INDO mRNA expression and tryptophan catabolism. Similarly, IL-4 but not IL-10 inhibited the cell surface expression of HLA-DR and CD2 induced by IFN-γ. Consistent with these findings we were able to detect by reverse transcription-PCR the expression of mRNA for different chains of IL-4 and IL-13 receptors (IL-4Rα, IL-13Rα1 and IL-13Rα2) but not for IL-10 receptor in the 2C4 and other human lung fibroblast cell lines (LL24 and MRC5). Together our results indicate that IL-4 and IL-13, but not IL-10, are implicated in the negative regulation of IFN-γ-induced anti-Toxoplasma activity in human cells from fibroblast lineage.