title: Alpha-galactosylceramide modulates the induction of indoleamine 2,3-dioxygenase in antigen presenting cells.
abstract: The glycolipid alpha-galactosylceramide (alpha-GalCer), when presented on CD1 molecules by antigen presenting cells (APCs) to invariant NKT (iNKT cells), is a potent immunomodulator. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the catabolism of L-tryptophan along the kynurenine pathway, is inducible in APC and represents one of the main endogenous mechanisms of T cell homeostasis, peripheral tolerance and immunosuppression. No data have been published yet on the effect of alpha-GalCer on IDO in APC. We aimed to determine if: (1) alpha-GalCer modulates IDO in APC; (2) the alpha-GalCer-induced effect on IDO correlates with the production by APC of active compounds; (3) the medium from alpha-GalCer-treated APC is able to stimulate iNKT cells. From our results alpha-GalCer alone did not modify IDO expression (RT-PCR) in APC, but when human peripheral blood mononuclear cells (PBMC), monocytes, and monocytic cell lines (THP-1), expressing high levels of CD1d, were treated with interferon-gamma (IFN-gamma) plus alpha-GalCer a significant potentiation of IDO transcription was measured. This effect was not induced by increased IFN-gamma release by APC, and it was functionally correlated with increased L-kynurenine (L-KYN) release by alpha-GalCer-treated CD1d-transfected THP-1 cells. The medium of these cells stimulated iNKT hybridoma cells to release interleukin (IL)-2, while alpha-GalCer alone resulted ineffective. The data demonstrate that alpha-GalCer: (1) does not induce IFN-gamma release by APC; (2) potentiates IFN-gamma-induced IDO expression and function in APC; (2) requires CD1d molecules for inducing these effects; (3) induces the release by APC of compounds active in stimulating iNKT cells.
authors.affiliation: DISCAFF Department, University of Piemonte Orientale, Via Bovio, 6, 28100 Novara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fallarini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Paoletti
authors.forename: Luigi
authors.initials: L
authors.lastname: Panza
authors.forename: Grazia
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000201:enzymology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000235:genetics; D005699:Galactosylceramides / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000201:enzymology; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D005699:Galactosylceramides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C493154:alpha-galactosylceramide; D007371:Interferon-gamma