期刊
MUCOSAL IMMUNOLOGY
卷 7, 期 6, 页码 1312-1325出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2014.19
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资金
- Japan Society for the Promotion of Science [25293172, 21229009, 24229005, 24659363]
- Japanese Society of Gastroenterology
- Special Coordination Funds by the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Astellas Pharma in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program
- National Institutes of Health
- Grants-in-Aid for Scientific Research [23590998, 25293172, 24659363] Funding Source: KAKEN
It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-kappa B activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
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