Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transactivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation

Abstract

Helicobacter pylori infection increases the risk of hyperplastic polyps and gastric cancer, but the mechanisms remain to be elucidated. H. pylori was recently shown to transactivate epidermal growth factor receptor (EGFR) through metalloprotease stimulation. The present study was designed to investigate the effect of interleukin-8 (IL-8) induced by H. pylori infection on EGFR transactivation and epithelial cell growth. H. pylori Sydney strain 1 (SS1) having wild-type cag(+)A was used. Phospho-EGFR assay was performed by immunoprecipitation using anti-human EGFR and anti-phosphotyrosine antibodies. DNA synthesis was evaluated by [3H]thymidine uptake using the human gastric cancer cell line, KATO III. H. pylori induced EGFR phosphorylation, and a disintegrin and metalloproteinase (ADAM) inhibitor, KB-R7785, completely suppressed EGFR phosphorylation. IL-8 also induced EGFR phosphorylation, while anti-IL-8 and anti-IL-8 receptor (CXCR1) neutralizing antibodies suppressed EGFR phosphorylation. [(3)H]Thymidine uptake analysis demonstrated that H. pylori increased DNA synthesis in gastric epithelial cells, and tyrosine kinase inhibitor, MEK inhibitor, and ADAM inhibitor suppressed the DNA synthesis induced by H. pylori. H. pylori-stimulated IL-8 accelerates processing of EGFR ligands through ADAM activation, and cleaved EGFR ligands bind and stimulate EGFR in paracrine and autocrine manners to induce cell proliferation. This may be one of the mechanisms of hyperplastic polyp and gastric cancer development in H. pylori-infected gastric mucosa.

Helicobacter pyloriCagA-Dependent Macrophage Migration Inhibitory Factor Produced by Gastric Epithelial Cells Binds to CD74 and Stimulates Procarcinogenic Events

“…Proinflammatory cytokines such as MIF and IL-8 have been attributed to increased proliferative signaling in a variety of systems (20,33,41,42). MIF has been shown to play an important role in the regulation of proinflammatory immune responses in inflammatory disorders, and proliferative responses in multiple cancer types.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…In vivo, ADAM-10 and -17 are overexpressed in antral mucosa during H. pylori infection and ADAM-9, -10, -12, -15, and -17 are increased in gastric tumours [150,151]. ADAM-10 acts through EGFR ligand shedding leading to gastric cell proliferation [151][152][153]. In colon carcinomas, ADAM-17 is overexpressed independently of tumour stage or grade and is involved in tumour growth and angiogenesis possibly via an autocrine/paracrine pathway implicating EGFR [154].…”

Macrophage Migration Inhibitory Factor and Interleukin-8 Produced by Gastric Epithelial Cells during Helicobacter pylori Exposure Induce Expression and Activation of the Epidermal Growth Factor Receptor

“…In addition to being a neutrophil chemotactic factor, IL-8 up-regulates GEC expression of CD74 (6) and has been shown to enhance the cell survival of some cell types (17,23). One way in which IL-8 may enhance cell survival and proliferation is by aiding in the transactivation of the epidermal growth factor receptor (EGFR) (18).…”