Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: Tampere vascular study

• Published in: Annals of medicine (Helsinki) Vol. 42; no. 1; p. 55
• Main Authors: Niinisalo, Petri, Oksala, Niku, Levula, Mari, Pelto-Huikko, Markku, Järvinen, Otso, Salenius, Juha-Pekka, Kytömäki, Leena, Soini, Juhani T, Kähönen, Mika, Laaksonen, Reijo, Hurme, Mikko, Lehtimäki, Terho
• Format: Journal Article
• Language: English
• Published: England 2010
• Subjects: Aged; Aged, 80 and over; Antigen-Presenting Cells - metabolism; Antigen-Presenting Cells - pathology; Antigens, CD - chemistry; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - chemistry; Antigens, Differentiation, T-Lymphocyte - metabolism; Atherosclerosis - enzymology; Atherosclerosis - immunology; Atherosclerosis - pathology; CD28 Antigens - metabolism; CTLA-4 Antigen; Female; Finland; Forkhead Transcription Factors - metabolism; Gene Expression; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inducible T-Cell Co-Stimulator Protein; Macrophages - immunology; Male; Middle Aged; Monocytes - immunology; T-Lymphocytes, Regulatory - immunology; Tryptophan - metabolism
• ISSN: 1365-2060
• DOI: 10.3109/07853890903321559

We aimed to characterize the expression of indoleamine 2,3-dioxygenase (IDO) or IDO-induced tryptophan degradation-dependent pathways, which may lead to suppression of T cells and possible protection against atherosclerosis. Expression of IDO and IDO-related pathway components was analyzed in advanced human atherosclerotic plaques (n = 24) and in non-atherosclerotic arteries (n = 6). Up-regulation of IDO and genes related to the IDO pathway was found to be pronounced in atherosclerotic plaques. Immunohistochemistry demonstrated IDO protein in the atheromatous core and co-distribution with monocyte-macrophages (CD68-positive cells). In gene-set enrichment analysis, the IDO pathway revealed a significant (false discovery rate (FDR) = 0.07) regulatory T cell, fork-head box protein 3 (FoxP3)-initiated CD28-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-inducible T cell co-stimulator (ICOS)-driven pathway leading to activation of IDO expression in antigen-presenting cells (APCs). Expression of these IDO pathway genes varied between 2.1- and 16.8-fold as compared to control tissues (P < 0.05 for all). IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis offering new viable therapeutic targets for the development of antiatherogenic immunosuppressive therapies.