TY - JOUR
T1 - NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis
AU - Kobayashi, Taku
AU - Steinbach, Erin C.
AU - Russo, Steven M.
AU - Matsuoka, Katsuyoshi
AU - Nochi, Tomonori
AU - Maharshak, Nitsan
AU - Borst, Luke B.
AU - Hostager, Bruce
AU - Garcia-Martinez, J. Victor
AU - Rothman, Paul B.
AU - Kashiwada, Masaki
AU - Sheikh, Shehzad Z.
AU - Murray, Peter J.
AU - Plevy, Scott E.
PY - 2014/2/15
Y1 - 2014/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84896735604&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1301819
DO - 10.4049/jimmunol.1301819
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C2 - 24442434
AN - SCOPUS:84896735604
SN - 0022-1767
VL - 192
SP - 1918
EP - 1927
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -