Activation of intercellular adhesion molecule 1 expression by Helicobacter pylori is regulated by NF-kappaB in gastric epithelial cancer cells.
Interactions between leukocytes and epithelial cells may play a key role in Helicobacter pylori-associated gastric mucosal inflammation. This process is mediated by various cell adhesion molecules. The present study examined the molecular mechanisms leading to H. pylori-induced epithelial cell intercellular adhesion molecule-1 (ICAM-1; also called CD54) expression. Coculture of epithelial cells with cytotoxin-associated gene pathogenicity island-positive (cag PAI(+)) H. pylori strains, but not with a cag PAI(-) strain or H. pylori culture supernatants, resulted in upregulation of steady-state mRNA levels and cell surface expression of ICAM-1. Coculture with H. pylori induced an increase in luciferase activity in cells which were transfected with a luciferase reporter gene linked to the 5'-flanking region of the ICAM-1 gene. H. pylori activated the ICAM-1 promoter via the NF-kappaB binding site. An inducible nuclear protein complex bound to the ICAM-1 NF-kappaB site and was identified as the NF-kappaB p50-p65 heterodimer. H. pylori induced the degradation of IkappaB-alpha, a major cytoplasmic inhibitor of NF-kappaB, and stimulated the expression of IkappaB-alpha mRNA. Pretreatment of epithelial cells with pyrrolidine dithiocarbamate, which blocks NF-kappaB activation, inhibited H. pylori-induced ICAM-1 expression. THP-1 macrophagic cells, peripheral blood mononuclear cells, and purified neutrophils adhered to H. pylori-infected epithelial cells to a greater extent than to uninfected cells. These results show that H. pylori directly induces expression of ICAM-1 on gastric epithelial cells in an NF-kappaB-dependent manner that may support leukocyte attachment during inflammation.
Mori
N
N
Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
Wada
A
A
Hirayama
T
T
Parks
T P
TP
Stratowa
C
C
Yamamoto
N
N
D000970:Antineoplastic Agents / Q000494:pharmacology; D001422:Bacterial Adhesion; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011759:Pyrrolidines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid