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

3-Hydroxyanthranilic acid (3-HAA), a metabolite of L-tryptophan, accumulate s in monocyte-derived cells (THP-I), but not in other cell lines tested (MR C 9. H4, U373MG, Wil-NS), following immune stimulation that induces indolea mine-2,3-dioxygenase (IDO), a rate-limiting enzyme in the L-tryptophan-kynu renine pathway. We examined whether metabolites of the L-tryptophan-kynuren ine pathway act to induce apoptosis in monocytes/macrophages. Of the L-tryp tophan metabolites tested, only 3-HAA at a concentration of 200 mu mol/L wa s found to induce apoptosis in THP-1 and U937 cells. The addition of ferrou s or manganese ions further enhanced apoptosis and free radical formation b y 3-HAA in these two types of cells. The apoptotic response induced by 3-HA A was significantly attenuated by the addition of antioxidant. alpha -tocop herol or Trolox (a water-soluble analogue of vitamin E). and the xanthine o xidase inhibitor, allopurinol. In addition. the 3-HAA-induced apoptotic res ponse 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 ferrou s or manganese ions. This different susceptibility to apoptosis inducer bet ween 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 synthesi zed proteins may de essential for apoptotic events. These results suggest t hat 3-HAA induces apoptosis in monocytes/macrophages under inflammatory or other pathophysiological conditions.