3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-γ

Toshiko Morita, Kuniaki Saito, Masao Takemura, Naoya Maekawa, Suwako Fujigaki, Hidehiko Fujii, Hisayasu Wada, Shoji Takeuchi, Akio Noma, Mitsuru Seishima

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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 μmol/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, α-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-γ (IFN-γ), 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-I and U937 cells may depend on the capacity of the cells for 3-HAA synthesis following IDO induction by IFN-γ. 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.

Original languageEnglish
Pages (from-to)242-251
Number of pages10
JournalAnnals of Clinical Biochemistry
Volume38
Issue number3
DOIs
Publication statusPublished - 22-05-2001

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry

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    Morita, T., Saito, K., Takemura, M., Maekawa, N., Fujigaki, S., Fujii, H., Wada, H., Takeuchi, S., Noma, A., & Seishima, M. (2001). 3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-γ. Annals of Clinical Biochemistry, 38(3), 242-251. https://doi.org/10.1258/0004563011900461