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

Giovanni Melillo, George W. Cox, Arya Biragyn, Lynn A. Sheffler, Luigi Varesio

Research output: Contribution to journalArticlepeer-review

Abstract

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)-γ alone. In contrast, a major increase of NOS mRNA expression was observed after treatment with IFN-γ 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-γ-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-γ 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.

Original languageEnglish
Pages (from-to)8128-8133
Number of pages6
JournalJournal of Biological Chemistry
Volume269
Issue number11
Publication statusPublished - Mar 18 1994

ASJC Scopus subject areas

  • Biochemistry

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