PICOLINIC-ACID, A CATABOLITE OF L-TRYPTOPHAN, IS A COSTIMULUS FOR THEINDUCTION OF REACTIVE NITROGEN INTERMEDIATE PRODUCTION IN MURINE MACROPHAGES

In this study we investigated the effects of picolinic acid, a catabol ite Of L-tryptophan, on the production Of L-arginine-derived reactive nitrogen intermediates in the murine macrophage cell line ANA-1. ANA-1 macrophages did not produce nitrite (NO2-) constitutively, but accumu lated detectable levels of NO2- on exposure to IFN-gamma. Picolinic ac id, although ineffective by itself, augmented IFN-gamma-induced NO2- p roduction. The activity of picolinic acid was evident at 1 mM and reac hed its maximum at 4 mM. Picolinic acid also augmented the IFN-gamma-d ependent expression of TNF-alpha mRNA, but did not appreciably affect the secretion of the TNF-alpha protein. Neutralizing concentrations of anti-TNF mAb completely abrogated IFN-gamma- and IFN-gamma plus rTNF- alpha-induced NO2- production in ANA-1 macrophages, but only decreased by approximately 50% the synergistic interaction between IFN-gamma an d picolinic acid. Although IL-4 inhibited the expression of IFN-gamma plus picolinic acid-induced TNF-alpha mRNA and protein, it only partia lly suppressed picolinic acid-dependent NO2- production. Therefore, pi colinic acid may affect NO2- production via both TNF-alpha-dependent a nd TNF-alpha-independent pathways. Overall, this study suggests that a mino acid catabolites may be important for the activation and the expr ession of effector functions by murine macrophages, and provides the f irst evidence of a possible connection between tryptophan and arginine metabolism.