Modulation of neopterin formation and tryptophan degradation by Th1-and Th2-derived cytokines in human monocytic cells

In order to examine the regulatory effects of major Th1-derived cytokines, such as IL-12, and Th2 cytokines, IL-4 and IL-10, on the formation of neopt erin and degradation of tryptophan, two metabolic pathways induced by inter feron-gamma (IFN-gamma) in human monocytes/macrophages, we investigated the human monocytic cell line THP-1, primary human macrophages, and peripheral blood mononuclear cells (PBMC). Neopterin formation and tryptophan degrada tion were induced similarly by IFN-gamma in all three cell types investigat ed, but the effects of interleukins were different between THP-1, primary m acrophages and PBMC. In PBMC, but not in THP-1 cells and primary macrophage s, IL-12 was found to be additive to the effects of IFN-gamma to superinduc e neopterin formation and tryptophan degradation. IL-4 and IL-10 reduced th e effects of IFN-gamma on monocytic cells, and both cytokines were additive ly antagonistic to IFN-gamma in PBMC and THP-1 cells. Finally, on preincuba tion, but not on addition of IL-12, the effects of IL-4 and IL-10 on PBMC c ould be abrogated, whereas no such effect was seen in THP-1 cells. The resu lts show that IL-12 up-regulates neopterin formation and tryptophan degrada tion by inducing additional IFN-gamma production by Th1 cells, while a dire ct effect of IL-12 on monocytes/macrophages appears to be absent. Similarly , IL-4 and IL-10 inhibit neopterin production and tryptophan degradation in PBMC by down-regulating Th1-type cytokine production and possibly also via direct deactivation of IFN-gamma effects towards monocytes/macrophages. Th e results clearly show how Th1 cell-mediated immunity may be up- or down-re gulated by endogenous cytokine production.