IAI Accepts, published online ahead of print on 26 October 2009

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Infect. Immun. doi:10.1128/IAI.00903-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Helicobacter pylori lipopolysaccharides upregulate Toll-like receptor 4 expression and proliferation of gastric epithelial cells via MEK1/2-ERK1/2 MAP kinase pathway

Shin-ichi Yokota^*, Tamaki Okabayashi, Michael Rehli, Nobuhiro Fujii, and Ken-ichi Amano

Department of Microbiology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556, Japan; Department of Hematology and Oncology, University of Regensburg, 93042 Regensburg, Germany; Bioscience Education and Research Center, Akita University, Akita 010-8543, Japan

^* To whom correspondence should be addressed. Email: syokota{at}sapmed.ac.jp.

Helicobacter pylori is recognized as an etiological agent of gastroduodenal diseases. H. pylori produces various toxic substances, including lipopolysaccharide (LPS). However, H. pylori LPS exhibits extremely weakly endotoxic activity compared to the typical LPS, such as that produced by Escherichia coli, which acts through Toll-like receptor 4 (TLR4) to induce inflammatory molecules. Gastric epithelial cell lines, MKN28 and MKN45, express TLR4 at very low levels, so they show very weak interleukin-8 production in response to E. coli LPS, but pretreatment with H. pylori LPS markedly enhanced IL-8 production induced by E. coli LPS by upregulating TLR4 via TLR2 and the MEK1/2-ERK1/2 pathway. The transcription factor NF-Y was activated by this signal and promoted transcription of the tlr4 gene. These MEK1/2-ERK1/2 signal-mediated activities were more potently activated by LPS carrying a weakly antigenic epitope, which is frequently found in gastric cancers, than by LPS carrying a highly antigenic epitope, which is associated with chronic gastritis. H. pylori LPS also augmented the proliferation rate of gastric epithelial cells via the MEK1/2-ERK1/2 pathway. H. pylori LPS may be a pathogenic factor causing gastric tumors by enhancing cell proliferation and inflammation via the MEK1/2-ERK1/2 MAP kinase cascade in gastric epithelial cells.