Picolinic acid, a catabolite of L-tryptophan, is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophages

In this study we investigated the effects of picolinic acid, a catabolite 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 accumulated detectable levels of NO₂ ^- on exposure to IFN-γ. Picolinic acid, although ineffective by itself, augmented IFN-γ-induced NO₂ ^- production. The activity of picolinic acid was evident at 1 mM and reached its maximum at 4 mM. Picolinic acid also augmented the IFN-γ-dependent expression of TNF-α mRNA, but did not appreciably affect the secretion of the TNF-α protein. Neutralizing concentrations of anti-TNF mAb completely abrogated IFN-γ- and IFN-γ plus rTNF-α-induced NO₂ ^- production in ANA-1 macrophages, but only decreased by approximately 50% the synergistic interaction between IFN-γ and picolinic acid. Although IL-4 inhibited the expression of IFN-γ plus picolinic acid-induced TNF-α mRNA and protein, it only partially suppressed picolinic acid-dependent NO₂ ^- production. Therefore, picolinic acid may affect NO₂ ^- production via both TNF-α-dependent and TNF-α-independent pathways. Overall, this study suggests that amino acid catabolites may be important for the activation and the expression of effector functions by murine macrophages, and provides the first evidence of a possible connection between tryptophan and arginine metabolism.