Tryptophan availability selectively limits NO-synthase induction in macrophages.

We studied the effects of tryptophan (TRP) availability on the synthesis and release of nitric oxide (NO) and tumor necrosis factor α (TNF-α) in interferon-γ (IFN-γ)-activated murine macrophages of the BAC1.2F5 cell line. IFN-γ (100 U/ml) not only increased the synthesis and release of NO and TNF-α from these cells but also induced indoleamine-2,3-dioxygenase, the rate-limiting enzyme of TRP catabolism. This led to an increased metabolic flow through the kynurenine pathway and significantly decreased TRP levels in macrophage incubation media. Low TRP concentrations in the media, however, modified IFN-γ effects. In TRP-“starved” cultures, in fact, the IFN-γ-mediated NO synthase induction was significantly reduced, and the increased TNF-α synthesis and release were not affected. Our results suggest that a reduced local TRP availability may modify macrophage function and possibly the outcome of immune responses.