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


RESULTS
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).


CONCLUSIONS
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.
Niinisalo
Petri
P
Department of Clinical Chemistry, University of Tampere, Medical School, and Tampere University Hospital, Centre for Laboratory Medicine, Tampere, Finland. petri.niinisalo@uta.fi
Oksala
Niku
N
Levula
Mari
M
Pelto-Huikko
Markku
M
Järvinen
Otso
O
Salenius
Juha-Pekka
JP
Kytömäki
Leena
L
Soini
Juhani T
JT
Kähönen
Mika
M
Laaksonen
Reijo
R
Hurme
Mikko
M
Lehtimäki
Terho
T
D000368:Aged; D000369:Aged, 80 and over; D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000473:pathology; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D005260:Female; D005387:Finland; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D060889:Inducible T-Cell Co-Stimulator Protein; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D060889:Inducible T-Cell Co-Stimulator Protein; D014364:Tryptophan; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; C556692:ICOS protein, human