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-gamma. Picolinic acid, although ineffective by itself, augmented IFN-gamma-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-gamma-dependent 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 and picolinic acid. Although IL-4 inhibited the expression of IFN-gamma plus picolinic acid-induced TNF-alpha mRNA and protein, it only partially suppressed picolinic acid-dependent NO2- production. Therefore, picolinic acid may affect NO2- production via both TNF-alpha-dependent and TNF-alpha-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.
Melillo
G
G
Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, NIH, MD 21702-1201.
Cox
G W
GW
Radzioch
D
D
Varesio
L
L
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D004357:Drug Synergism; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000378:metabolism*; D010848:Picolinic Acids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014364:Tryptophan / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D019323:omega-N-Methylarginine
D009573:Nitrites; D010848:Picolinic Acids; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D014364:Tryptophan; D001120:Arginine; C030614:picolinic acid