Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.
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.
Katakura
Kyoko
K
Department of Medicine, UCSD, La Jolla, California 92093-0663, USA.
Lee
Jongdae
J
Rachmilewitz
Daniel
D
Li
Gloria
G
Eckmann
Lars
L
Raz
Eyal
E
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
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