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 neopterin and degradation of tryptophan, two metabolic pathways induced by interferon‐gamma (IFN‐γ) 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 degradation were induced similarly by IFN‐γ in all three cell types investigated, but the effects of interleukins were different between THP‐1, primary macrophages and PBMC. In PBMC, but not in THP‐1 cells and primary macrophages, IL‐12 was found to be additive to the effects of IFN‐γ to superinduce neopterin formation and tryptophan degradation. IL‐4 and IL‐10 reduced the effects of IFN‐γ on monocytic cells, and both cytokines were additively antagonistic to IFN‐γ in PBMC and THP‐1 cells. Finally, on preincubation, but not on addition of IL‐12, the effects of IL‐4 and IL‐10 on PBMC could be abrogated, whereas no such effect was seen in THP‐1 cells. The results show that IL‐12 up‐regulates neopterin formation and tryptophan degradation by inducing additional IFN‐γ production by Th1 cells, while a direct 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‐γ effects towards monocytes/macrophages. The results clearly show how Th1 cell‐mediated immunity may be up‐ or down‐regulated by endogenous cytokine production.