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

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

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 1

Production of chemokines by HT-29 cells stimulated with MDP or iE-DAP.

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Production of chemokines by HT-29 cells stimulated with MDP or iE-DAP. (...
(A) IP-10, I-TAC, IL-8, and MDC production by iE-DAP–stimulated HT-29 cells without IFN-γ pretreatment. HT-29 cells (106/ml in 6-well plates) were stimulated with NOD1 ligand (iE-DAP; 1, 10, or 100 μg/ml) or NOD2 ligand (MDP; 1, 10, or 100 μg/ml) for 24 hours. Cultured supernatants were harvested and assayed. (B) NOD1 and NOD2 expression in HT-29 cells stimulated with TNF (10 or 100 ng/ml) or IFN-γ (10 or 100 ng/ml) for 24 hours. Whole cell lysates from HT-29 cells transfected with NOD1 and NOD2 cDNA were used for positive controls of NOD1 and NOD2 expression, respectively. (C) HT-29 cells (106/ml in 6-well plates) were cultured with IFN-γ or TNF (10 or 100 ng/ml) for 24 hours and then cultured with iE-DAP (1 or 10 μg/ml) or MDP (1 or 10 μg/ml) for another 24 hours. Cultured supernatants were harvested and assayed for the presence of IP-10, I-TAC, IL-8, and MDC by ELISA. Results shown are representative of 2 or 3 studies. Results are expressed as mean ± SD. *P < 0.05; **P < 0.01 compared with cells cultured with medium alone.