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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/G1004    most recent 00096.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Uno, K. Articles by Yoshimura, T. Search for Related Content PubMed PubMed Citation Articles by Uno, K. Articles by Yoshimura, T.

INFLAMMATION/IMMUNITY/MEDIATORS

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

¹Research Project of Biofunctional Reactive Species, Yamagata Promotional Organization for Industrial Technology, Yamagata; ²Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai; ³Cancer Detection Center, Miyagi Cancer Society, Sendai; and ⁴School of Veterinary Medicine, Azabu University, Sagamihara, Japan; and ⁵Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

Submitted 23 February 2007 ; accepted in final form 30 August 2007

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-B (NF-B), were analyzed in normal mouse gastric mucosal GSM06 cells following stimulation with H. pylori-LPS and interferon-. Specific inhibitors for mitogen-activated protein kinases, NF-B, 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-B 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-B 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.

lipopolysaccharide; nitric oxide; stomach