Regulatory role of tryptophan degradation pathway in HLA-G expression by human monocyte-derived dendritic cells.
Dendritic cells (DC) are strong inducers of immunity but they can also be tolerogenic. During monocyte differentiation to DC the immunosuppressive indoleamine-2,3-dioxygenase (IDO) is induced. IDO degrades Trp to kynurenine, which is further metabolized to 3-hydroxyanthranilic acid. DC can also express mRNA and protein of the tolerogenic molecule HLA-G, but there is no surface expression. We studied the effect of the Trp degrading pathway on HLA-G expression by DC. When monocytes were differentiated to immature DC in presence of either Trp or its metabolites kynurenine or 3-hydroxyanthranilic acid they expressed cell surface HLA-G, and Trp also increased shedding of HLA-G1. Trp induced HLA-G cell surface expression when present during maturation with IFN-gamma+LPS, but not with TNF-alpha. Kynurenine increased HLA-G expression in both TNF-alpha and IFN-gamma+LPS matured DC, and 3-hydroxyanthranilic acid had a very weak effect on HLA-G cell surface expression when present during maturation. Shedding of HLA-G1 was more pronounced in IFN-gamma+LPS-matured DC than in immatured DC. Maturation with IFN-gamma+LPS in presence of kynurenine also increased HLA-G5 secretion. The mechanism involved seems to be post-translational as mRNA and cellular HLA-G protein content was not increased with Trp, kynurenine or 3-hydroxyanthranilic acid treatments. Finally, immature DC preincubated with Trp, kynurenine and 3-hydroxyanthranilic acid have after a decreased capacity to stimulate T cells in mixed lymphocyte reaction. In IFN-gamma+LPS-matured DC this decreased capacity was obtained with kynurenine and 3-hydroxyanthranilic acid. These results suggest that IDO can induce HLA-G cell surface expression in DC, and that these two molecules can cooperate in the immune suppression.
Department of Clinical Biochemistry, Clínica Universitaria de Navarra, Av. Pío XII 36, 31008 Pamplona, Spain.
Ana S
AS
López
Estibaliz
E
Alegre
Joël
J
LeMaoult
Edgardo
E
Carosella
Alvaro
A
González
D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007737:Kynurenine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan