title: Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.
abstract: The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human inflammatory bowel disease and in experimental models of colitis, there is an increased expression of the enzyme IDO. IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine trinitrobenzene sulfonic acid model of colitis, inhibition of this enzyme leads to worsened disease severity, suggesting that IDO acts as a natural break in limiting colitis. In this investigation, we show that induction of IDO-1 by a TLR-9 agonist, immunostimulatory (ISS) DNA, critically contributes to its colitis limiting capacities. ISS DNA induces intestinal expression of IDO-1 but not the recently described paralog enzyme IDO-2. This induction occurred in both epithelial cells and in subsets of CD11c(+) and CD11b(+) cells of the lamina propria, which also increase after ISS-oligodeoxynucleotide. Signaling required for intestinal IDO-1 induction involves IFN-dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the trinitrobenzene sulfonic acid and dextran sodium sulfate models of colitis, we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histological correlates of colitis in these models were improved by administration of the TLR-9 agonist; however, when the function of IDO is inhibited, the colitis limiting effects of ISS-oligodeoxynucleotide were abrogated. These findings support the possibility that targeted induction of IDO-1 is an approach deserving further investigation as a therapeutic strategy for diseases of intestinal inflammation.
authors.affiliation: Division of Gastroenterology, Washington University, St Louis, MO 63110, USA. mciorba@wustl.edu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Ciorba
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Bettonville
authors.forename: Keely G
authors.initials: KG
authors.lastname: McDonald
authors.forename: Richard
authors.initials: R
authors.lastname: Metz
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Newberry
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D004247:DNA / Q000494:pharmacology; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D005455:Fluorescent Antibody Technique; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000201:enzymology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D000276:Adjuvants, Immunologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007527:Isoenzymes; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D014302:Trinitrobenzenesulfonic Acid; D004247:DNA; D016264:Dextran Sulfate