Toll-like receptor 9-induced type I IFN protects mice from experimental colitis

J Clin Invest. 2005 Mar;115(3):695-702. doi: 10.1172/JCI22996.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colon / cytology
  • Colon / immunology
  • Colon / pathology
  • Culture Media, Conditioned
  • Cytokines / immunology
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dextran Sulfate / administration & dosage
  • Dextran Sulfate / toxicity
  • Disease Models, Animal
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Indicators and Reagents / administration & dosage
  • Indicators and Reagents / toxicity
  • Interferon-alpha / immunology*
  • Interferon-beta / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, SCID
  • Myeloid Differentiation Factor 88
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Interferon alpha-beta
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • Toll-Like Receptor 9

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Culture Media, Conditioned
  • Cytokines
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Indicators and Reagents
  • Interferon-alpha
  • MYD88 protein, human
  • Membrane Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nuclear Proteins
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interferon
  • TLR9 protein, human
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • RAG-1 protein
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • Dextran Sulfate
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases