Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 8, Pages 4649-4655Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1003888
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Funding
- National Institutes of Health [RO1 DK54452, R01 CA127279, R01 GM08372, R21 AI076921, RO1 AI54821]
- Gastroenterology Research Training Grant [T32 DK007737]
- National Research Service Award [F32 DK083186]
- National Gnotobiotic Rodent Resource Center [P40 RR018603]
- Center for Gastrointestinal Biology and Disease [P30 DK034987]
- Crohn's and Colitis Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Uehara Memorial Foundation
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Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b(+) lamina propria mononuclear cells from Nfil3(-/-) mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14(+) lamina propria mononuclear cells from Crohn's disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10(-/-) mice transitioned from germfree to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases. The Journal of Immunology, 2011, 186: 4649-4655.
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