Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells

Kaname Uno, Katsuaki Kato, Tomoaki Atsumi, Takehito Suzuki, Jun Yoshitake, Hidetoshi Morita, Shuichi Ohara, Yashige Kotake, Tooru Shimosegawa, Tetsuhiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

Cell-surface Toll-like receptors (TLRs) initiate innate immune responses, such as inducible nitric oxide synthase (iNOS) induction, to microorganisms' surface pathogens. TLR2 and TLR4 play important roles in gastric mucosa infected with Helicobacter pylori (H. pylori), which contains lipopolysaccharide (LPS) as a pathogen. The present study investigates their physiological roles in the innate immune response of gastric epithelial cells to H. pylori-LPS. Changes in the expression of iNOS, TLR2, and TLR4, as well as downstream activation of mitogen-activated protein kinases and nuclear factor-κB (NF-κB), were analyzed in normal mouse gastric mucosal GSM06 cells following stimulation with H. pylori-LPS and interferon-γ. Specific inhibitors for mitogen-activated protein kinases, NF-κB, and small interfering RNA for TLR2 or TLR4 were employed. The immunohistochemistry of TLR2 was examined in human gastric mucosa. H. pylori-LPS stimulation induced TLR2 in GSM06 cells, but TLR4 was unchanged. TLR2 induction resulted from TLR4 signaling that propagated through extracellular signal-related kinase and NF-κB activation, as corroborated by the decline in TLR4 expression on small interfering RNA treatment and pretreatment with inhibitors. The induction of iNOS and the associated nitric oxide production in response to H. pylori-LPS stimulation were inhibited by declines in not only TLR4 but also TLR2. Increased expression of TLR2 was identified in H. pylori-infected human gastric mucosa. TLR4 signaling initiated by H. pylori-LPS and propagated via extracellular signal-regulated kinase and NF-κB activation induced TLR2 expression in gastric epithelial cells. Induced TLR2 cooperated with TLR4 to amplify iNOS induction. This positive correlation may constitute a mechanism for stimulating the innate immune response against various bacterial pathogens, including H. pylori-LPS.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume293
Issue number5
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

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Toll-Like Receptor 2
Nitric Oxide Synthase Type II
Helicobacter pylori
Stomach
Epithelial Cells
Gastric Mucosa
Innate Immunity
Mitogen-Activated Protein Kinases
Small Interfering RNA
Toll-Like Receptors
Extracellular Signal-Regulated MAP Kinases
Interferons
Lipopolysaccharides
Helicobacter pylori lipopolysaccharide
Nitric Oxide
Phosphotransferases
Immunohistochemistry

Keywords

  • Lipopolysaccharide
  • Nitric oxide
  • Stomach

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells. / Uno, Kaname; Kato, Katsuaki; Atsumi, Tomoaki; Suzuki, Takehito; Yoshitake, Jun; Morita, Hidetoshi; Ohara, Shuichi; Kotake, Yashige; Shimosegawa, Tooru; Yoshimura, Tetsuhiko.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 293, No. 5, 11.2007.

Research output: Contribution to journalArticle

Uno, Kaname ; Kato, Katsuaki ; Atsumi, Tomoaki ; Suzuki, Takehito ; Yoshitake, Jun ; Morita, Hidetoshi ; Ohara, Shuichi ; Kotake, Yashige ; Shimosegawa, Tooru ; Yoshimura, Tetsuhiko. / Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2007 ; Vol. 293, No. 5.
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AU - Yoshitake, Jun

AU - Morita, Hidetoshi

AU - Ohara, Shuichi

AU - Kotake, Yashige

AU - Shimosegawa, Tooru

AU - Yoshimura, Tetsuhiko

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