Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid

J Biol Chem. 1994 Mar 18;269(11):8128-33.


Picolinic acid, a catabolite of L-tryptophan, is a potent co-stimulatory agent for the induction of tumoricidal activity and the production of L-arginine-dependent reactive nitrogen intermediates (RNI) in murine macrophages. We studied whether picolinic acid could affect nitric-oxide synthase (NOS) expression at the gene level in the macrophage cell line ANA-1. NOS mRNA was neither constitutively expressed nor induced by treatment with picolinic acid alone. However, low levels of NOS mRNA were induced by interferon (IFN)-gamma alone. In contrast, a major increase of NOS mRNA expression was observed after treatment with IFN-gamma plus picolinic acid. The synergism was already detectable after 5-6 h and increased up to 20 h of treatment. The ability of picolinic acid to augment IFN-gamma-dependent NOS mRNA expression was associated with a parallel increase in transcription, as demonstrated by nuclear run-on experiments. Protein synthesis was required for the induction of NOS mRNA because addition of cycloheximide dramatically reduced IFN-gamma plus picolonic acid-induced NOS mRNA expression. Finally, interleukin-4 significantly decreased IFN-gamma plus picolinic acid-induced NOS mRNA expression and NOS transcription. These data provide evidence of a molecular event connecting arginine and tryptophan metabolic pathways in the generation of RNI, and they indicate that picolinic acid can induce transcriptional activation of gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / biosynthesis*
  • Animals
  • Blotting, Northern
  • Cell Line
  • Cell Nucleus / metabolism
  • Drug Synergism
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Interferon-gamma / pharmacology*
  • Kinetics
  • Macrophages / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase
  • Picolinic Acids / pharmacology*
  • RNA, Messenger / biosynthesis*
  • Recombinant Proteins
  • Transcription, Genetic / drug effects


  • Picolinic Acids
  • RNA, Messenger
  • Recombinant Proteins
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases
  • picolinic acid