title: 3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma.
abstract: 3-Hydroxyanthranilic acid (3-HAA), a metabolite of L-tryptophan, accumulates in monocyte-derived cells (THP-1), but not in other cell lines tested (MRC-9, H4, U373MG, Wil-NS), following immune stimulation that induces indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme in the L-tryptophan kynurenine pathway. We examined whether metabolites of the L-tryptophan-kynurenine pathway act to induce apoptosis in monocytes/macrophages. Of the L-tryptophan metabolites tested, only 3-HAA at a concentration of 200 micromol/L was found to induce apoptosis in THP-1 and U937 cells. The addition of ferrous or manganese ions further enhanced apoptosis and free radical formation by 3-HAA in these two types of cells. The apoptotic response induced by 3-HAA was significantly attenuated by the addition of antioxidant, alpha-tocopherol or Trolox (a water-soluble analogue of vitamin E), and the xanthine oxidase inhibitor, allopurinol. In addition, the 3-HAA-induced apoptotic response was slightly attenuated by catalase, but not by superoxide dismutase (SOD), indicating that generation of hydrogen peroxide is involved in this response. Interferon-gamma (IFN-gamma), an inducer of IDO, potently induced apoptosis in THP-1 cells, but not in U937 cells, in the presence of ferrous or manganese ions. This different susceptibility to apoptosis inducer between THP-1 and U937 cells may depend on the capacity of the cells for 3-HAA synthesis following IDO induction by IFN-gamma. Furthermore, apoptosis was suppressed by cycloheximide in THP-1 cells, suggesting that newly synthesized proteins may be essential for apoptotic events. These results suggest that 3-HAA induces apoptosis in monocytes/macrophages under inflammatory or other pathophysiological conditions.
authors.affiliation: Department of Laboratory Medicine, Gifu University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Morita
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Takemura
authors.forename: N
authors.initials: N
authors.lastname: Maekawa
authors.forename: S
authors.initials: S
authors.lastname: Fujigaki
authors.forename: H
authors.initials: H
authors.lastname: Fujii
authors.forename: H
authors.initials: H
authors.lastname: Wada
authors.forename: S
authors.initials: S
authors.lastname: Takeuchi
authors.forename: A
authors.initials: A
authors.lastname: Noma
authors.forename: M
authors.initials: M
authors.lastname: Seishima
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D013053:Spectrophotometry; D014364:Tryptophan / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D000975:Antioxidants; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014969:Xanthine Oxidase