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 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.
Ramon
H E
HE
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Riling
C R
CR
Bradfield
J
J
Yang
B
B
Hakonarson
H
H
Oliver
P M
PM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D015848:Interleukin-5 / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058408:Th1-Th2 Balance; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015848:Interleukin-5; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases