Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transactivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation |
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Authors: | Takashi Joh MD Hiromi Kataoka MD PhD Satoshi Tanida Katsushi Watanabe MD Tadayuki Ohshima MD PhD Makoto Sasaki MD Haruhisa Nakao MD Hirotaka Ohhara MD Shigeki Higashiyama PhD Makoto Itoh MD |
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Institution: | (1) Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku Nagoya, 467-8601, Japan;(2) Department of Medical Biochemistry, Ehime University School of Medicine, Japan |
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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. 3H]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. |
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Keywords: | Helicobacter pylori interleukin-8 epidermal growth factor receptor a disintegrin and metalloproteinase (ADAM) |
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