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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism
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Cells, Cultured
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Colitis / chemically induced
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Colitis / immunology*
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Colon / cytology
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Colon / immunology
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Colon / pathology
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Culture Media, Conditioned
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Cytokines / immunology
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DNA-Activated Protein Kinase
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dextran Sulfate / administration & dosage
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Dextran Sulfate / toxicity
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Disease Models, Animal
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Indicators and Reagents / administration & dosage
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Indicators and Reagents / toxicity
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Interferon-alpha / immunology*
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Interferon-beta / immunology*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Mice, SCID
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Myeloid Differentiation Factor 88
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Nuclear Proteins
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Interferon alpha-beta
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Receptors, Cell Surface / agonists
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Receptors, Interferon / genetics
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Receptors, Interferon / metabolism
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Toll-Like Receptor 9
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Culture Media, Conditioned
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Cytokines
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DNA-Binding Proteins
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Homeodomain Proteins
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Indicators and Reagents
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Interferon-alpha
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MYD88 protein, human
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Nuclear Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interferon
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TLR9 protein, human
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Tlr9 protein, mouse
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Toll-Like Receptor 9
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RAG-1 protein
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Receptor, Interferon alpha-beta
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Interferon-beta
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Dextran Sulfate
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases