Journal Article

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

Raz, Eyal, Li, Gloria, Eckmann, Lars, Katakura, Kyoko, Lee, Jongdae, Rachmilewitz, Daniel

2005

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adaptor Proteins, Signal Transducing / Animals / Antigens, Differentiation - genetics / Antigens, Differentiation - metabolism / Biomedical research / Bone marrow / Cells, Cultured / Colitis - chemically induced / Colitis - immunology / Colon - cytology / Colon - immunology / Colon - pathology / Culture Media, Conditioned / Cytokines - immunology / Dendritic cells / Dextran Sulfate - administration & dosage / Dextran Sulfate - toxicity / Disease Models, Animal / DNA-Activated Protein Kinase / DNA-Binding Proteins - agonists / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / Immune system / Indicators and Reagents - administration & dosage / Indicators and Reagents - toxicity / Inflammation / Inflammatory bowel disease / Interferon-alpha - immunology / Interferon-beta - immunology / Kinases / Ligands / Lymphocytes / 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