Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice.
OBJECTIVE
Indoleamine 2,3-dioxygenase (IDO), an interferon gamma-induced intracellular enzyme, inhibits lymphocyte proliferation through tryptophan degradation. IDO is highly expressed in the mammalian intestine. We sought to determine whether IDO played a regulatory role in the T-cell helper 1 (Th1)-mediated trinitrobenzene sulfonic acid (TNBS) model of colitis.


METHODS
Intrarectal TNBS was given to SJL/J mice along with either placebo or a specific IDO inhibitor. IDO protein and mRNA expression were assessed by Western blotting and real-time PCR. Colonic lamina propria mononuclear cells (LPMNCs) were isolated, fractionated, and cultured, in the presence and absence of IFN-gamma, to determine the cell type(s) expressing IDO.


RESULTS
IDO is expressed by professional antigen-presenting cells in the lamina propria. Induction of TNBS colitis resulted in a significant increase in IDO mRNA (P = 0.005) and protein expression. IDO inhibition during TNBS colitis resulted in an 80% mortality compared with 10% for placebo-treated animals (P = 0.0089). IDO inhibition resulted in a more severe colitis both histologically and morphologically (P < 0.05) and significantly increased colonic proinflammatory cytokine expression compared with placebo-treated animals.


CONCLUSIONS
IDO is expressed in the normal colon and is up-regulated in the setting of TNBS colitis. Inhibition of IDO during TNBS colitis resulted in increased mortality and an augmentation of the normal inflammatory response. These findings suggest that IDO plays an important role in the down-regulation of Th1 responses within the gastrointestinal tract.
Gurtner
Gregory J
GJ
Division of Gastroenteroloyg, Washington University School of Medicine, St. Louis, Missouri 63110, USA. ggurtner@im.wustl.edu
Newberry
Rodney D
RD
Schloemann
Suzanne R
SR
McDonald
Keely G
KG
Stenson
William F
WF
D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D014366:Tryptophan Oxygenase