Helicobacter pylori-stimulated interleukin-8 (IL-8) promotes cell proliferation through transactivation of epidermal growth factor receptor (EGFR) by disintegrin and metalloproteinase (ADAM) activation.
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.
Joh
Takashi
T
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Kataoka
Hiromi
H
Tanida
Satoshi
S
Watanabe
Katsushi
K
Ohshima
Tadayuki
T
Sasaki
Makoto
M
Nakao
Haruhisa
H
Ohhara
Hirotaka
H
Higashiyama
Shigeki
S
Itoh
Makoto
M
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics*; D005419:Flavonoids / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D015533:Transcriptional Activation / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology
D005419:Flavonoids; D006877:Hydroxamic Acids; D016209:Interleukin-8; C107086:KB R7785; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004247:DNA; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D048369:MAP Kinase Kinase 1; D051722:ADAM Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005998:Glycine