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NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway
Tomohiro Watanabe, … , Atsushi Kitani, Warren Strober
Tomohiro Watanabe, … , Atsushi Kitani, Warren Strober
Published April 12, 2010
Citation Information: J Clin Invest. 2010;120(5):1645-1662. https://doi.org/10.1172/JCI39481.
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Research Article Immunology Article has an altmetric score of 1

NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

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Abstract

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor–associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-β production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-β or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN–mediated protection from H. pylori and possibly other mucosal infections.

Authors

Tomohiro Watanabe, Naoki Asano, Stefan Fichtner-Feigl, Peter L. Gorelick, Yoshihisa Tsuji, Yuko Matsumoto, Tsutomu Chiba, Ivan J. Fuss, Atsushi Kitani, Warren Strober

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Figure 2

Activation of NF-κB and MAPK in HT-29 cells stimulated with iE-DAP.

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Activation of NF-κB and MAPK in HT-29 cells stimulated with iE-DAP.
(A) ...
(A) HT-29 cells were either untreated or treated with 100 ng/ml of IFN-γ (24 hours) and then stimulated with 10 or 100 μg/ml of iE-DAP. Whole cell extracts prepared from the stimulated cells at the indicated time points after stimulation with iE-DAP were then subjected to Western blot analysis. Extracts from HT-29 cells treated with 50 ng/ml TNF were used as positive controls. (B) NF-κB activation was assessed by EMSA. Nuclear extracts were prepared from IFN-γ–untreated or IFN-γ–treated HT-29 cells stimulated with iE-DAP (10 or 100 μg/ml) at the indicated time points. Nuclear extracts from TNF-treated (50 ng/ml) cells were used as a positive control. (C and D) Translocation of NF-κB subunits (p65, p50) in nuclear extracts was determined by Transfactor assay. Nuclear extracts from HT-29 cells treated with 50 ng/ml of TNF for 1 hour were used as positive controls for p65 and p50. HT-29 cells were pre-incubated with (D) or without (C) IFN-γ. (E) Wild-type (Ikkb+/+) or IKKβ-deficient (Ikkb–/–) MEFs were stimulated with iE-DAP (100 μg/ml) or TNF (10 ng/ml) for 24 hours. Cultured supernatants were subjected to an IP-10 assay. Results are expressed as means ± SD. **P < 0.01 compared with wild-type cells.

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

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