title: Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses.
abstract: Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori-induced expression of the intestinal epithelial-specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori-induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori-infected patients to limit their risks of accumulating precancerous gastric lesions.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. asanon@med.tohoku.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imatani
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fushiya
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Jin
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ara
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Uno
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koike
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology*; D016481:Helicobacter Infections / Q000150:complications* / Q000378:metabolism; D016480:Helicobacter pylori; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014157:Transcription Factors