The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility

Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein that regulates Itch, an E3 ubiquitin ligase that ubiquitylates JunB, thereby preventing interleukin (IL)-4 and IL-5 production. Mice lacking Ndfip1 or Itch develop T helper type 2 (T(H)2)-mediated inflammation in the skin and lungs an...

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Bibliographic Details
Published in:Mucosal immunology 2011-05, Vol.4 (3), p.314-324
Main Authors: Ramon, H E, Riling, C R, Bradfield, J, Yang, B, Hakonarson, H, Oliver, P M
Format: Article
Language:English
Subjects:
Animals
Carrier Proteins - genetics
Carrier Proteins - immunology
Carrier Proteins - metabolism
Cell Movement - genetics
Cell Movement - immunology
Cells, Cultured
Eosinophils - immunology
Eosinophils - metabolism
Eosinophils - pathology
Genetic Predisposition to Disease
Inflammation
Inflammatory Bowel Diseases - immunology
Intercellular Signaling Peptides and Proteins
Interleukin-5 - immunology
Intestinal Mucosa - metabolism
Intestines - immunology
Intestines - pathology
Membrane Proteins - genetics
Membrane Proteins - immunology
Membrane Proteins - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Polymorphism, Single Nucleotide
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
T-Lymphocytes - pathology
Th1-Th2 Balance
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - immunology
Ubiquitin-Protein Ligases - metabolism
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Summary:Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein that regulates Itch, an E3 ubiquitin ligase that ubiquitylates JunB, thereby preventing interleukin (IL)-4 and IL-5 production. Mice lacking Ndfip1 or Itch develop T helper type 2 (T(H)2)-mediated inflammation in the skin and lungs and die prematurely. In this study we show that Ndfip1-/- mice also develop inflammation in the gastrointestinal tract. Inflammation is characterized by infiltration of eosinophils and T cells and is accompanied by a failure to gain weight. T cells are both necessary and sufficient for eosinophil recruitment and inflammation. This is because Ndfip1-/- T cells become activated and produce IL-5. Itch mutant mice develop much less severe gastrointestinal inflammation, suggesting that Ndfip1 regulation of Itch cannot entirely account for this phenotype and that Ndfip1 has both Itch-dependent and Itch-independent roles. Ndfip1 may also regulate human disease. We found single-nucleotide polymorphisms in the Ndfip1 locus that associate with inflammatory bowel disease. Taken together, our data support a role for Ndfip1 in gastrointestinal inflammation in both mice and humans.
ISSN:1933-0219
1935-3456
DOI:10.1038/mi.2010.69