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Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development.
Cole, Jennifer E; Astola, Nagore; Cribbs, Adam P; Goddard, Michael E; Park, Inhye; Green, Patricia; Davies, Alun H; Williams, Richard O; Feldmann, Marc; Monaco, Claudia.
Afiliação
  • Cole JE; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Astola N; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Cribbs AP; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Goddard ME; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Park I; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Green P; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Davies AH; Imperial Vascular Unit, Division of Surgery and Cancer, Imperial College, London W6 8RF, United Kingdom.
  • Williams RO; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
  • Feldmann M; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom; marc.feldmann@kennedy.ox.ac.uk claudia.monaco@kennedy.ox.ac.uk.
  • Monaco C; Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom; marc.feldmann@kennedy.ox.ac.uk claudia.monaco@kennedy.ox.ac.uk.
Proc Natl Acad Sci U S A ; 112(42): 13033-8, 2015 Oct 20.
Article em En | MEDLINE | ID: mdl-26438837
Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE(-/-) mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE(-/-) mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not l-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE(-/-) mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Aterosclerose / Indolamina-Pirrol 2,3,-Dioxigenase Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Aterosclerose / Indolamina-Pirrol 2,3,-Dioxigenase Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article