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Gnotobiotic IL-10^–/–;NF-B^EGFP Mice Reveal the Critical Role of TLR/NF-B Signaling in Commensal Bacteria-Induced Colitis¹

Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27510

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-B activation in a model of commensal bacteria-induced T cell-mediated colitis. A NF-B reporter gene mouse (NF-B^EGFP) (EGFP, enhanced GFP) was crossed to the colitogenic susceptible strain IL-10^–/– and derived into germfree conditions using embryo-transfer technology. Germfree IL-10^wt/wt;NF-B^EGFP and IL-10^–/–;NF-B^EGFP 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-B^EGFP mice developed severe inflammation by 7 wk. Macroscopic analysis showed elevated EGFP expression throughout the colon of bacteria-associated IL-10^–/–;NF-B^EGFP mice. Confocal microscopy analysis revealed EGFP-positive enterocytes during the early phase of bacterial colonization (1 wk) in both IL-10^wt/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-B inhibitor BAY 11-7085 attenuated E. faecalis/E. coli-induced EGFP expression and development of colitis. Additionally, E. faecalis/E. coli-induced NF-B 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-B signaling derived mostly from mucosal immune cells. Blocking TLR-induced NF-B activity may represent an attractive strategy to treat immune-mediated intestinal inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R0I DK 47700, Crohn’s and Colitis Foundation of America Grants, and a American Gastroenterological Association Fiterman Basic Research Award (to C.J.); the Crohn’s and Colitis Foundation of America Fellowship (to T.K.); National Institutes of Health Grant P30 DK03498; and National Gnotobiotic Rodent Research Center Grant P40 R018603.

² Current address: Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, 110-744 Korea.

³ Address correspondence and reprint requests to Dr. Christian Jobin, University of North Carolina, CB 7032, Department of Medicine 7341B, Medical Biomolecular Research Building, Chapel Hill, NC 27599. E-mail address: Job{at}med.unc.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; EGFP, enhanced GFP; BMDC, bone marrow-derived dendritic cell; ChIP, chromatin immunoprecipitation; LPMNC, lamina propria mononuclear cell; LPL, lamina propria lymphocyte; IEL, intestinal epithelial lymphocyte; wt, wild type.

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