Proinflammatory cytokine interferon-γ increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid β peptide 1-42: implications for the pathogenesis of Alzheimer's disease

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme of the kynurenine pathway of tryptophan metabolism, ultimately leading to production of the excitotoxin quinolinic acid (QUIN) by monocytic cells. In the Tg2576 mouse model of Alzheimer's disease, systemic inflammation induced by lipopolysaccharide leads to an increase in IDO expression and QUIN production in microglia surrounding amyloid plaques. We examined whether the IDO over-expression in microglia could be mediated by brain proinflammatory cytokines induced during the peripheral inflammation using THP-1 cells and peripheral blood mononuclear cells (PBMC) as models for microglia. THP-1 cells pre-treated with 5-25 mu M amyloid beta peptide (A beta) (1-42) but not with A beta (1-40) or A beta (25-35) became an activated state as indicated by their morphological changes and enhanced adhesiveness. IDO expression was only slightly increased in the reactive cells but strongly enhanced following treatment with proinflammatory cytokine interferon-gamma (IFN-gamma) but not with interleukin-1 beta, tumor necrosis factor-alpha, or interleukin-6 at 100 U/mL. The concomitant addition of A beta (1-42) with IFN-gamma was totally ineffective, indicating that A beta pre-treatment is prerequisite for a high IDO expression. The priming effect of A beta (1-42) for the IDO induction was also observed for PBMC. These findings suggest that IFN-gamma induces IDO over-expression in the primed microglia surrounding amyloid plaques.