NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag PAI-positive-Helicobacter pylori infection.
OBJECTIVE
To elucidate the sequential gene expression profile in AGS cells co-cultured with wild-type Helicobacter pylori (H pylori) as a model of H pylori-infected gastric epithelium, and to further examine the contribution of cag-pathogenicity islands (cagPAI)-coding type IV secretion system and the two pathways, nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinases (ERK) on wild-type H pylori-induced gene expression.


METHODS
Gene expression profiles induced by H pylori were evaluated in AGS gastric epithelial cells using cDNA microarray, which were present in the 4 600 independent clones picked up from the human gastric tissue. We also analyzed the contribution of NF-kappaB and ERK signaling on H pylori-induced gene expression by using inhibitors of specific signal pathways. The isogenic mutant with disrupted cagE (Delta cagE) was used to elucidate the role of cagPAI-encoding type IV secretion system in the gene expression profile.


RESULTS
According to the expression profile, the genes were classified into four clusters. Among them, the clusters characterized by continuous upregulation were most conspicuous, and it contained many signal transducer activity-associated genes. The role of cagPAI on cultured cells was also investigated using isogenic mutant cagE, which carries non-functional cagPAI. Then the upregulation of more than 80% of the induced genes (476/566) was found to depend on cagPAI. Signal transducer pathway through NF-kappaB or ERK are the major pathways which are known to be activated by cagPAI-positive H pylori. The role of these pathways in the whole signal activation by cagPAI-positive H pylori was analyzed. The specific inhibitors against NF-kappaB or ERK pathway blocked the activation of gene expression in 65% (367/566) or 76% (429/566) of the genes whose activation appealed to depend on cagPAI.


CONCLUSIONS
These results suggest that more than half of the genes induced by cagPAI-positive H pylori depend on NF-kappaB and ERK signaling activation, and these pathways may play a role in the gene expression induced by host-bacterial interaction which may associate with H pylori-related gastro-duodenal diseases.
Shibata
Wataru
W
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. wshibata-tky@umin.ac.jp
Hirata
Yoshihiro
Y
Yoshida
Haruhiko
H
Otsuka
Motoyuki
M
Hoshida
Yujin
Y
Ogura
Keiji
K
Maeda
Shin
S
Ohmae
Tomoya
T
Yanai
Ayako
A
Mitsuno
Yuzo
Y
Seki
Naohiko
N
Kawabe
Takao
T
Omata
Masao
M
D001426:Bacterial Proteins / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D044404:Genomic Islands / Q000502:physiology; D016481:Helicobacter Infections / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*
D001426:Bacterial Proteins; D016328:NF-kappa B; C103937:PicB protein, Helicobacter pylori; D048049:Extracellular Signal-Regulated MAP Kinases