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 alpha (TNF-alpha) in interferon-gamma (IFN-gamma)-activated murine macrophages of the BAC1.2F5 cell line. IFN-gamma (100 U/ml) not only increased the synthesis and release of NO and TNF-alpha 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-gamma effects. In TRP-"starved" cultures, in fact, the IFN-gamma-mediated NO synthase induction was significantly reduced, and the increased TNF-alpha 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.
Chiarugi
Alberto
A
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Rovida
Elisabetta
E
Dello Sbarba
Persio
P
Moroni
Flavio
F
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D007737:Kynurenine / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009243:NAD / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D014364:Tryptophan / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014366:Tryptophan Oxygenase / Q000096:biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D009569:Nitric Oxide; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D001120:Arginine; D014366:Tryptophan Oxygenase; D019001:Nitric Oxide Synthase