Proinflammatory cytokine interferon-gamma increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid beta 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 muM amyloid beta peptide (Abeta) (1-42) but not with Abeta (1-40) or Abeta (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-1beta, tumor necrosis factor-alpha, or interleukin-6 at 100 U/mL. The concomitant addition of Abeta (1-42) with IFN-gamma was totally ineffective, indicating that Abeta pre-treatment is prerequisite for a high IDO expression. The priming effect of Abeta (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.
Yamada
Akiko
A
National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan.
Akimoto
Hidetoshi
H
Kagawa
Syota
S
Guillemin
Gilles J
GJ
Takikawa
Osamu
O
D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D007737:Kynurenine / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D007737:Kynurenine; D007371:Interferon-gamma