title: Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.
abstract: Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1-/- but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-alpha/beta) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-beta mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-alpha/beta receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.
authors.affiliation: Department of Medicine, UCSD, La Jolla, California 92093-0663, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Katakura
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Daniel
authors.initials: D
authors.lastname: Rachmilewitz
authors.forename: Gloria
authors.initials: G
authors.lastname: Li
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000276:immunology; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000633:toxicity; D016898:Interferon-alpha / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D017077:Culture Media, Conditioned; D016207:Cytokines; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007202:Indicators and Reagents; D016898:Interferon-alpha; C507779:MYD88 protein, human; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C064658:RAG-1 protein; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D016264:Dextran Sulfate; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases