Helicobacter pylori induces matrix metalloproteinase-9 through activation of nuclear factor kappaB.
OBJECTIVE
Matrix metalloproteinases (MMPs), enzymes capable of degrading extracellular matrix components, are believed to be active in connective tissue remodeling associated with various physiologic processes and in pathologic conditions. The aim of this study was to analyze the molecular mechanism responsible for Helicobacter pylori-mediated MMP expression.


METHODS
Expression of MMP messenger RNA and MMP activity were assessed by reverse-transcription polymerase chain reaction and zymography, respectively. Chloramphenicol acetyltransferase assay was used to monitor activation of the MMP-9 gene promoter, and electrophoretic mobility shift assay was used to explore the binding of transcription factors to this promoter. Gastric tissue samples were immunohistochemically stained for MMP-9.


RESULTS
H. pylori induced MMP-9 expression in 2 gastric epithelial cell lines but had no effect on MMP-2. Induction of MMP-9 was dependent on an intact cag pathogenicity island. Activation of the MMP-9 promoter by H. pylori occurred through the action of nuclear factor kappaB. Transfection of kinase-deficient mutants of IkappaB kinase and nuclear factor kappaB-inducing kinase inhibited H. pylori-mediated activation of MMP-9. MMP-9 expression was higher in epithelial cells of H. pylori-positive tissue compared with those of H. pylori-negative tissue.


CONCLUSIONS
H. pylori induced activation of nuclear factor kappaB through an intracellular signaling pathway that involved IkappaB kinase and nuclear factor kappaB-inducing kinase, leading to MMP-9 gene transcription. MMP-9 induction by H. pylori may play an important role in gastric inflammation, ulcer formation, and carcinogenesis.
Mori
Naoki
N
Department of Virology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. n-mori@med.u-ryukyu.ac.jp
Sato
Hiroshi
H
Hayashibara
Toshihisa
T
Senba
Masachika
M
Geleziunas
Romas
R
Wada
Akihiro
A
Hirayama
Toshiya
T
Yamamoto
Naoki
N
D002478:Cells, Cultured; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology / Q000382:microbiology; D005753:Gastric Mucosa / Q000166:cytology / Q000382:microbiology; D005756:Gastritis / Q000201:enzymology / Q000382:microbiology; D015971:Gene Expression Regulation, Enzymologic; D016481:Helicobacter Infections / Q000201:enzymology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000166:cytology / Q000382:microbiology; D014158:Transcription, Genetic
D016328:NF-kappa B; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9