NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis

Taku Kobayashi, Erin C. Steinbach, Steven M. Russo, Katsuyoshi Matsuoka, Tomonori Nochi, Nitsan Maharshak, Luke B. Borst, Bruce Hostager, J. Victor Garcia-Martinez, Paul B. Rothman, Masaki Kashiwada, Shehzad Z. Sheikh, Peter J. Murray, Scott E. Plevy

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28 Citations (Scopus)

Abstract

NFIL3 is a transcription factor that regulates multiple immunologic functions. In myeloid cells, NFIL3 is IL-10 inducible and has a key role as a repressor of IL-12p40 transcription. NFIL3 is a susceptibility gene for the human inflammatory bowel diseases. In this article, we describe spontaneous colitis in Nfil3-/- mice. Mice lacking both Nfil3 and Il10 had severe early-onset colitis, suggesting that NFIL3 and IL-10 independently regulate mucosal homeostasis. Lymphocytes were necessary for colitis, because Nfil3/Rag1 double-knockout mice were protected from disease. However, Nfil3/Rag1 double-knockout mice adoptively transferred with wild-type CD4+ T cells developed severe colitis compared with Rag1-/- recipients, suggesting that colitis was linked to defects in innate immune cells. Colitis was abrogated in Nfil3/Il12b double-deficient mice, identifying Il12b dysregulation as a central pathogenic event. Finally, germ-free Nfil3 -/- mice do not develop colonic inflammation. Thus, NFIL3 is a microbiota-dependent, IL-10-independent regulator of mucosal homeostasis via IL-12p40.

Original languageEnglish
Pages (from-to)1918-1927
Number of pages10
JournalJournal of Immunology
Volume192
Issue number4
DOIs
Publication statusPublished - 2014 Feb 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kobayashi, T., Steinbach, E. C., Russo, S. M., Matsuoka, K., Nochi, T., Maharshak, N., Borst, L. B., Hostager, B., Garcia-Martinez, J. V., Rothman, P. B., Kashiwada, M., Sheikh, S. Z., Murray, P. J., & Plevy, S. E. (2014). NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis. Journal of Immunology, 192(4), 1918-1927. https://doi.org/10.4049/jimmunol.1301819