Helicobacter pylori Lipopolysaccharides Upregulate Toll-Like Receptor 4 Expression and Proliferation of Gastric Epithelial Cells via the MEK1/2-ERK1/2 Mitogen-Activated Protein Kinase Pathway

Abstract

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. The gastric epithelial cell lines MKN28 and MKN45 express TLR4 at very low levels, so they show very weak interleukin-8 (IL-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 mitogenactivated protein kinase cascade in gastric epithelial cells.

Helicobacter pylori Lipopolysaccharide as a Possible Pathogenic Factor for Gastric Carcinogenesis

“…In concordance with the report of Chochi et al (2008), H. pylori LPS was shown to upregulate the cell growth rate of gastric epithelial cell lines (Yokota et al, 2010) (Fig. 5-D).…”

“…Activation of the MEK-ERK MAP kinase pathway via TLR2 activates NF-Y, and the NF-Y transcriptionally activates various cell cycle regulation genes, such as cyclin A1, cyclin B2, and E2F1. However, there are some contradictions between our report (Yokota et al, 2010) and the report of Chochi et al (2008). We found that the mitogenic activity was H. pylorispecific.…”

“…We found that the mitogenic activity was H. pylorispecific. With respect to TLR usage, Chochi et al (2008) showed that anti-TLR4 antibody can neutralize the activity; however, we found that downregulation of TLR2 expression by siRNA diminished the activity (Yokota et al, 2010). The novel activities of H. pylori LPS reported by us (Yokota et al, 2010) (Fig.…”

“…We found that pretreatment of gastric epithelial cell lines with H. pylori LPS enhanced the expression of TLR4 and also the responsiveness to E. coli LPS (Fig. 5-C) (Yokota et al, 2010). These gastric epithelial cell lines express markedly low levels of TLR4.…”

Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5

“…In gastric cancers, TLR2 and TLR4 are known to promote cell proliferation (23,30). However, a recent clinical study revealed that TLR5 was strongly expressed in tumor cells of all examined patients (n=22) with gastric carcinoma (24), which drove us to examine the role of TLR5 on the growth of gastric cancer.…”