RRC ID 43108
Author Uno K, Kato K, Atsumi T, Suzuki T, Yoshitake J, Morita H, Ohara S, Kotake Y, Shimosegawa T, Yoshimura T.
Title Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells.
Journal Am J Physiol Gastrointest Liver Physiol
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-kappaB (NF-kappaB), were analyzed in normal mouse gastric mucosal GSM06 cells following stimulation with H. pylori-LPS and interferon-gamma. Specific inhibitors for mitogen-activated protein kinases, NF-kappaB, 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-kappaB 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-kappaB 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.
Volume 293(5)
Pages G1004-12
Published 2007-11-1
DOI 10.1152/ajpgi.00096.2007
PII 00096.2007
PMID 17855767
MeSH Cell Line Gastric Mucosa / drug effects Gastric Mucosa / microbiology Gastric Mucosa / pathology Gastric Mucosa / physiology* Gene Expression Regulation Helicobacter Infections / pathology Helicobacter Infections / physiopathology Helicobacter pylori / immunology Helicobacter pylori / physiology* Humans Lipopolysaccharides / toxicity Nitric Oxide Synthase Type II / biosynthesis Nitric Oxide Synthase Type II / genetics* RNA, Small Interfering / genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Toll-Like Receptor 2 / deficiency Toll-Like Receptor 2 / genetics* Toll-Like Receptor 4 / deficiency Toll-Like Receptor 4 / genetics*
IF 3.725
Times Cited 63
Human and Animal Cells