NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis.
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.
Center for Gastrointestinal Biology and Diseases, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
Taku
T
Kobayashi
Erin C
EC
Steinbach
Steven M
SM
Russo
Katsuyoshi
K
Matsuoka
Tomonori
T
Nochi
Nitsan
N
Maharshak
Luke B
LB
Borst
Bruce
B
Hostager
J Victor
JV
Garcia-Martinez
Paul B
PB
Rothman
Masaki
M
Kashiwada
Shehzad Z
SZ
Sheikh
Peter J
PJ
Murray
Scott E
SE
Plevy
D019264:Adoptive Transfer; D000818:Animals; D029681:Arabidopsis Proteins / Q000096:biosynthesis; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000382:microbiology*; D016753:Interleukin-10 / Q000235:genetics*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D029681:Arabidopsis Proteins; D050976:Basic-Leucine Zipper Transcription Factors; C556062:IL10 protein, mouse; C508841:Il23a protein, mouse; D053762:Interleukin-12 Subunit p40; D053760:Interleukin-23 Subunit p19; D008565:Membrane Proteins; C497441:Nfil3 protein, mouse; C471640:Rma1 protein, Arabidopsis; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10