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Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis
Tomohiro Watanabe, … , Atsushi Kitani, Warren Strober
Tomohiro Watanabe, … , Atsushi Kitani, Warren Strober
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):545-559. https://doi.org/10.1172/JCI33145.
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Research Article Gastroenterology

Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis

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Abstract

The mechanisms underlying the susceptibility of individuals with caspase recruitment domain 15 (CARD15) mutations and corresponding abnormalities of nucleotide-binding oligomerization domain 2 (NOD2) protein to Crohn disease are still poorly understood. One possibility is based on previous studies showing that muramyl dipeptide (MDP) activation of NOD2 negatively regulates TLR2 responses and that absence of such regulation leads to heightened Th1 responses. We now report that administration of MDP protects mice from the development of experimental colitis by downregulating multiple TLR responses, not just TLR2. The basis of these in vivo findings was suggested by in vitro studies of DCs, in which we showed that prestimulation of cells with MDP reduces cytokine responses to multiple TLR ligands and this reduction is dependent on enhanced IFN regulatory factor 4 (IRF4) activity. Further studies of mouse models of colitis showed that this inhibitory role of IRF4 does in fact apply to MDP-mediated protection from colitis, since neither IRF4-deficient mice nor mice treated with siRNA specific for IRF4 were protected. These findings indicate that MDP activation of NOD2 regulates innate responses to intestinal microflora by downregulating multiple TLR responses and suggest that the absence of such regulation leads to increased susceptibility to Crohn disease.

Authors

Tomohiro Watanabe, Naoki Asano, Peter J. Murray, Keiko Ozato, Prafullakumar Tailor, Ivan J. Fuss, Atsushi Kitani, Warren Strober

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Figure 3

MDP administration prevents DSS colitis.

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MDP administration prevents DSS colitis.
NOD2-intact (NOD2+/+) and NOD2-...
NOD2-intact (NOD2+/+) and NOD2-deficient (NOD2–/–) mice were treated with drinking water containing 4% DSS for 6 days (days 0–5). At the early phase of colitis induction (days 0, 1, 2), mice were administered MDP (i.p.) or PBS every day. (A) Changes of body weight in PBS- or MDP-injected mice. *P < 0.05; **P < 0.01, time point values of NOD2-intact mice administered MDP compared with NOD2-intact mice administered PBS. (B) Serum amyloid A (SAA) levels and colitis scores of mice (see Methods) on day 7. SAA levels were determined by ELISA. *P < 0.05, NOD2-intact mice administered MDP compared with mice administered PBS.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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