NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity

Taku Kobayashi, Katsuyoshi Matsuoka, Shehzad Z. Sheikh, Houda Z. Elloumi, Nobuhiko Kamada, Tadakazu Hisamatsu, Jonathan J. Hansen, Kevin R. Doty, Scott D. Pope, Stephen T. Smale, Toshifumi Hibi, Paul B. Rothman, Masaki Kashiwada, Scott E. Plevy

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)4649-4655
Number of pages7
JournalJournal of Immunology
Volume186
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15

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Mucosal Immunity
Interleukin-12
Microbiota
Macrophages
Interleukin-10
Mucous Membrane
Bacterial Artificial Chromosomes
Leucine Zippers
Chromatin Immunoprecipitation
Colitis
Ulcerative Colitis
Inflammatory Bowel Diseases
Crohn Disease
Small Interfering RNA
Colon
Homeostasis
Transcription Factors
Binding Sites
Maintenance
adjuvant P40

ASJC Scopus subject areas

  • Immunology

Cite this

Kobayashi, T., Matsuoka, K., Sheikh, S. Z., Elloumi, H. Z., Kamada, N., Hisamatsu, T., ... Plevy, S. E. (2011). NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. Journal of Immunology, 186(8), 4649-4655. https://doi.org/10.4049/jimmunol.1003888

NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. / Kobayashi, Taku; Matsuoka, Katsuyoshi; Sheikh, Shehzad Z.; Elloumi, Houda Z.; Kamada, Nobuhiko; Hisamatsu, Tadakazu; Hansen, Jonathan J.; Doty, Kevin R.; Pope, Scott D.; Smale, Stephen T.; Hibi, Toshifumi; Rothman, Paul B.; Kashiwada, Masaki; Plevy, Scott E.

In: Journal of Immunology, Vol. 186, No. 8, 15.04.2011, p. 4649-4655.

Research output: Contribution to journalArticle

Kobayashi, T, Matsuoka, K, Sheikh, SZ, Elloumi, HZ, Kamada, N, Hisamatsu, T, Hansen, JJ, Doty, KR, Pope, SD, Smale, ST, Hibi, T, Rothman, PB, Kashiwada, M & Plevy, SE 2011, 'NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity', Journal of Immunology, vol. 186, no. 8, pp. 4649-4655. https://doi.org/10.4049/jimmunol.1003888
Kobayashi T, Matsuoka K, Sheikh SZ, Elloumi HZ, Kamada N, Hisamatsu T et al. NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. Journal of Immunology. 2011 Apr 15;186(8):4649-4655. https://doi.org/10.4049/jimmunol.1003888
Kobayashi, Taku ; Matsuoka, Katsuyoshi ; Sheikh, Shehzad Z. ; Elloumi, Houda Z. ; Kamada, Nobuhiko ; Hisamatsu, Tadakazu ; Hansen, Jonathan J. ; Doty, Kevin R. ; Pope, Scott D. ; Smale, Stephen T. ; Hibi, Toshifumi ; Rothman, Paul B. ; Kashiwada, Masaki ; Plevy, Scott E. / NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. In: Journal of Immunology. 2011 ; Vol. 186, No. 8. pp. 4649-4655.
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AU - Smale, Stephen T.

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AU - Plevy, Scott E.

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