Helicobacter pyloriAugments Growth of Gastric Cancers via the Lipopolysaccharide-Toll-like Receptor 4 Pathway whereas Its Lipopolysaccharide Attenuates Antitumor Activities of Human Mononuclear Cells

Abstract

Purpose: Helicobacter pylori is reportedly involved in the development of gastric cancer. We investigated the mechanisms by which H. pylori affects gastric cancer growth and antitumor immunities in the host, focusing on H. pylori^derived lipopolysaccharide (LPS). Experimental Design: H. pylori and four gastric cancer cell lines (MKN28, MKN45, NUGC3, and KATOIII) were used.We examined the effect of H. pylori or its LPS stimulationon cancer growth and the involvement of the H. pylori LPS-toll-like receptor 4 (TLR4) pathway. We also examined the cytotoxicities of H. pylori/LPS^stimulatedhumanmononuclear cells (MNC) against gastric cancer cells and the effect of H. pylori LPS stimulation on cytokine production by MNC. Results: H. pylori, as well as its LPS, augmented the growth of gastric cancers, all of which expressed TLR4. Neutralization of TLR4 almost completely abrogated the H. pylori^induced proliferative activity of cancer cells. Escherichia coli LPS also augmented cancer growth via the LPS-TLR4 pathway. However, only H. pylori^derived LPS attenuated the cytotoxicity of MNC against gastric cancer cells. Stimulation with H. pylori/LPS also down-regulated perforin production in cancer cell^cocultured CD56 + natural killer cells. H. pylori LPS induced neither interleukin-12 nor IFN-g production by MNC, although E. coli LPS did induce production of both significantly. Nevertheless, interleukin-12 stimulation restored the IFN-g^producing capacity of H. pylori LPS^stimulated MNC. Conclusion: H. pylori augmented the growth of gastric cancers via the LPS-TLR4 pathway, whereas it attenuated the antitumor activity and IFN-g^mediated cellular immunity of MNC. H. pylori infection might thereby promote proliferation and progression of gastric cancers.

Helicobacter pylori Lipopolysaccharide as a Possible Pathogenic Factor for Gastric Carcinogenesis

“…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.…”

“…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).…”

“…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.…”

“…Chochi et al (2008) reported that both H. pylori and E. coli LPS enhance the proliferation rate of gastric cancer cell lines. However, they also showed that H. pylori LPS, but not E. coli LPS, attenuates the cytotoxicity of mononuclear cells against gastric cancer cells, and downregulates perforin production in CD56 + natural killer cells cocultured with gastric cancer cells.…”

The C-Terminal Disulfide Bonds of Helicobacter pylori GroES Are Critical for IL-8 Secretion via the TLR4-Dependent Pathway in Gastric Epithelial Cells

“…It has been demonstrated that TLR4, TLR5, and TLR9 expressed on human gastric epithelium are involved in the innate immune response to H. pylori (50). Furthermore, several studies indicated that TLR2 (51-53) and TLR4 (44,49,54) play a role in H. pylori infection. However, a study showed that both TLR2 and TLR5, but not TLR4, are involved in H. pylori-induced cytokine production (48).…”