Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis.
OBJECTIVE
Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO.


METHODS
Arthritis was induced by immunization with type II collagen. After induction of arthritis, the expression of IDO was analyzed by quantitative reverse transcription-polymerase chain reaction. The effect of IDO deficiency on collagen-induced arthritis was assessed in vivo by administration of 1-methyltryptophan and clinical and histologic evaluation of IDO-deficient mice. The requirement for IDO activation was bypassed by administration of L-kynurenine.


RESULTS
IDO was induced in lymph node dendritic cells after collagen immunization. Systemic inhibition of tryptophan catabolism during active arthritis increased disease severity. Conversely, bypassing the requirement for tryptophan degradation by the administration of L-kynurenine resulted in amelioration of arthritis. Furthermore, IDO-deficient mice showed a higher incidence of arthritis and exacerbated disease severity compared with IDO-competent mice. Such increased disease activity in IDO-deficient mice correlated early with increased production of the proinflammatory cytokines interferon-gamma and interleukin-17 by lymph node T cells and later with increased infiltration of Th1 and Th17 cells in the inflamed joints.


CONCLUSIONS
Our data indicate that the induction of IDO controls the accumulation of Th1 and Th17 pathogenic T cells at the site of inflammation during collagen-induced arthritis. Therefore, manipulation of the kynurenine pathway of tryptophan degradation provides the potential for therapeutic intervention in rheumatoid arthritis.
Criado
Gabriel
G
Kennedy Institute of Rheumatology, Imperial College London, London, UK. g.criado@imperial.ac.uk
Simelyte
Egle
E
Inglis
Julia J
JJ
Essex
David
D
Williams
Richard O
RO
D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000032:analysis / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007737:Kynurenine / Q000097:blood / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D010446:Peptide Fragments / Q000096:biosynthesis; D018417:Th1 Cells / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D010446:Peptide Fragments; C069261:interferon gamma (1-39); D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan