RGD Reference Report - Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium. - Rat Genome Database

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Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium.

Authors: Richardson, WM  Sodhi, CP  Russo, A  Siggers, RH  Afrazi, A  Gribar, SC  Neal, MD  Dai, S  Prindle T, JR  Branca, M  Ma, C  Ozolek, J  Hackam, DJ 
Citation: Richardson WM, etal., Gastroenterology. 2010 Sep;139(3):904-17, 917.e1-6. doi: 10.1053/j.gastro.2010.05.038. Epub 2010 May 24.
RGD ID: 8547529
Pubmed: PMID:20580721   (View Abstract at PubMed)
PMCID: PMC2930126   (View Article at PubMed Central)
DOI: DOI:10.1053/j.gastro.2010.05.038   (Journal Full-text)

BACKGROUND & AIMS: Factors that regulate enterocyte apoptosis in necrotizing enterocolitis (NEC) remain incompletely understood, although Toll-like receptor-4 (TLR4) signaling in enterocytes plays a major role. Nucleotide-binding oligomerization domain-2 (NOD2) is an immune receptor that regulates other branches of the immune system, although its effects on TLR4 in enterocytes and its role in NEC remain unknown. We now hypothesize that activation of NOD2 in the newborn intestine inhibits TLR4, and that failure of NOD2 signaling leads to NEC through increased TLR4-mediated enterocyte apoptosis. METHODS: The effects of NOD2 on enterocyte TLR4 signaling and intestinal injury and repair were assessed in enterocytes lacking TLR4 or NOD2, in mice with intestinal-specific wild-type or dominant-negative TLR4 or NOD2, and in mice with NEC. A protein array was performed on NOD2-activated enterocytes to identify novel effector molecules involved. RESULTS: TLR4 activation caused apoptosis in newborn but not adult small intestine or colon, and its intestinal expression was influenced by NOD2. NOD2 activation inhibited TLR4 in enterocytes, but not macrophages, and reversed the effects of TLR4 on intestinal mucosal injury and repair. Protection from TLR4-induced enterocyte apoptosis by NOD2 required a novel pathway linking NOD2 with the apoptosis mediator second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (SMAC-DIABLO), both in vitro and in vivo. Strikingly, activation of NOD2 reduced SMAC-DIABLO expression, attenuated the extent of enterocyte apoptosis, and reduced the severity of NEC. CONCLUSIONS: These findings reveal a novel inhibitory interaction between TLR4 and NOD2 signaling in enterocytes leading to the regulation of enterocyte apoptosis and suggest a therapeutic role for NOD2 in the protection of intestinal diseases such as NEC.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
perinatal necrotizing enterocolitis  ISONod2 (Mus musculus)8547529; 8547529 RGD 
perinatal necrotizing enterocolitis  IMP 8547529 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Nod2  (nucleotide-binding oligomerization domain containing 2)

Genes (Mus musculus)
Nod2  (nucleotide-binding oligomerization domain containing 2)

Genes (Homo sapiens)
NOD2  (nucleotide binding oligomerization domain containing 2)


Additional Information