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Gnotobiotic IL-10-/-;NF-kappa B(EGFP) mice reveal the critical role of TLR/NF-kappa B signaling in commensal bacteria-induced colitis

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Authors
Karrasch, Thomas; Kim, Joo-Sung; Muhlbauer, Marcus; Magness, Scott T; Jobin, Christian
Issue Date
2007-05-04
Publisher
American Association of Immunologists
Citation
J Immunol. 2007 May 15;178(10):6522-32.
Keywords
AnimalsColitis/genetics/*immunology/pathologyEnterococcus faecalis/immunologyEscherichia coli Infections/genetics/immunology/pathologyFemaleGenes, ReporterGerm-Free Life/*immunologyGram-Positive Bacterial Infections/genetics/immunology/pathologyGreen Fluorescent Proteins/biosynthesis/*geneticsInterleukin-10/*deficiency/*genetics/physiologyMaleMiceMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsNF-kappa B/*genetics/physiologySignal Transduction/genetics/*immunologyToll-Like Receptors/*physiology
Abstract
Commensal bacteria and TLR signaling have been associated with the maintenance of intestinal homeostasis in dextran sodium sulfate-induced intestinal injury. The aim of this study was to determine the in vivo role of TLR/NF-kappaB activation in a model of commensal bacteria-induced T cell-mediated colitis. A NF-kappaB reporter gene mouse (NF-kappaBEGFP) (EGFP, enhanced GFP) was crossed to the colitogenic susceptible strain IL-10-/- and derived into germfree conditions using embryo-transfer technology. Germfree IL-10wt/wt;NF-kappaBEGFP and IL-10-/-;NF-kappaBEGFP mice (wt, wild type) were dual associated with the nonpathogenic commensal bacteria strains Enterococcus faecalis and Escherichia coli. EGFP was detected using macroimaging, confocal microscopy, and flow cytometry. IL-10-/-;MyD88-/- mice were used to assess E. faecalis/E. coli-induced TLR-dependent signaling and IL-23 gene expression. Dual-associated IL-10-/-;NF-kappaBEGFP mice developed severe inflammation by 7 wk. Macroscopic analysis showed elevated EGFP expression throughout the colon of bacteria-associated IL-10-/-;NF-kappaBEGFP mice. Confocal microscopy analysis revealed EGFP-positive enterocytes during the early phase of bacterial colonization (1 wk) in both IL-10wt/wt and IL-10-/- mice, while the signal shifted toward lamina propria T cells, dendritic cells, neutrophils, and macrophages in IL-10-/- mice during colitis (7 wk). The NF-kappaB inhibitor BAY 11-7085 attenuated E. faecalis/E. coli-induced EGFP expression and development of colitis. Additionally, E. faecalis/E. coli-induced NF-kappaB signaling and IL-23 gene expression were blocked in bone marrow-derived dendritic cells derived from IL-10-/-;MyD88-/- mice. We conclude that bacteria-induced experimental colitis involves the activation of TLR-induced NF-kappaB signaling derived mostly from mucosal immune cells. Blocking TLR-induced NF-kappaB activity may represent an attractive strategy to treat immune-mediated intestinal inflammation.
ISSN
0022-1767 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17475882

http://hdl.handle.net/10371/29588
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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