title: Effects of interferons beta or gamma on neopterin biosynthesis and tryptophan degradation by human alveolar macrophages in vitro: synergy with lipopolysaccharide.
abstract: Interferons can induce neopterin biosynthesis and tryptophan degradation in monocytic cells. Indoleamine 2,3-dioxygenase (IDO), an inducible cellular enzyme, metabolizes tryptophan to N-formyl-L-kynurenine. Tryptophan degradation has been linked to interferon-mediated inhibition of replication by intracellular pathogens and inhibition of cancer cell proliferation. We evaluated the ability of the recombinant human interferons beta ser and gamma to stimulate neopterin production and tryptophan degradation in vitro by alveolar macrophages (AM) obtained from normal volunteers by bronchoalveolar lavage. Additionally, because other biologic response modifiers such as lipopolysaccharide (LPS) can also stimulate monocytic cells to produce increased amounts of neopterin and degrade tryptophan, we evaluated the effects of LPS on interferon-induced neopterin production and tryptophan degradation by AM. Both interferon-gamma (IFN-gamma) and interferon-beta (IFN-beta) induced neopterin production and tryptophan degradation by AM with corresponding inhibition of intracellular replication by Chlamydia psittaci in AM, but IFN-gamma was a more potent inducer of these responses than IFN-beta. LPS enhanced neopterin production and tryptophan degradation by interferon-exposed cells. This effect was particularly evident at lower concentrations of interferon, and LPS synergy was more pronounced with IFN-beta than IFN-gamma. Concentrations of LPS that alone had no stimulatory effect on tryptophan degradation synergistically enhanced the induction of IDO activity by lower concentrations of interferon. These studies suggest that IFN-gamma stimulates human AM to produce neopterin and degrade tryptophan more potently than IFN-beta, and that low concentrations of LPS can synergistically enhance such effects of interferons on tissue macrophage metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of Wisconsin, Madison.
authors.forename: K C
authors.initials: KC
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Cornwell
authors.forename: J M
authors.initials: JM
authors.lastname: Carlin
authors.forename: C
authors.initials: C
authors.lastname: Powers
authors.forename: A
authors.initials: A
authors.lastname: Irizarry
authors.forename: G I
authors.initials: GI
authors.lastname: Byrne
authors.forename: E C
authors.initials: EC
authors.lastname: Borden
mesh_terms: D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002691:Chlamydophila psittaci; D004357:Drug Synergism; D004790:Enzyme Induction; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000378:metabolism*; D019798:Neopterin; D009956:Psittacosis / Q000517:prevention & control; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000096:biosynthesis
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D001708:Biopterins; D019798:Neopterin; D016899:Interferon-beta; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase