title: Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells.
abstract: NF-kappaB is a critical regulator of genes involved in inflammation. Gastric epithelial cells and macrophages are considered the main sources of pro-inflammatory cytokines. We investigated NF-kappaB activation by Helicobacter pylori in MKN45 gastric epithelial cells and THP-1 monocytic cells. Although, cag pathogenicity island (PAI)-positive H. pylori (wild type) activated NF-kappaB in both cells, isogenic mutant of cagE (DeltacagE) activated it only in THP-1 cells. Supernatant from the wild type culture could activate NF-kappaB in THP-1 cells but not in MKN45 cells. High density cDNA array analysis revealed that mRNA expression of NF-kappaB-regulated genes such as interleukin (IL)-8, tumor necrosis factor-alpha (TNFalpha), and IL-1beta was significantly up-regulated by the wild type in both cells, whereas it was up-regulated by DeltacagE only in THP-1 cells. Experiments using CD14-neutralizing antibody and IL-1 receptor-associated kinase (IRAK) assay showed that both wild type and DeltacagE H. pylori activated NF-kappaB through CD14 and IRAK in THP-1 cells but not in MKN45 cells. Macrophages from C3H/HeJ mice carrying point mutation in the Toll-like receptor 4 (TLR4) gene showed decreased NF-kappaB activation and TNFalpha secretion compared with C3H/HeN mouse macrophage when treated with H. pylori. In conclusion, H. pylori-induced NF-kappaB activation in epithelial cells is dependent on cag PAI and contact but does not involve CD14 and IRAK, whereas in macrophage/monocytic cells it is independent of cag PAI or contact but involves CD14 and TLR4.
authors.affiliation: Department of Gastroenterology, Faculty of Medicine, University of Tokyo. 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. MAEDA-2IM@h.u-tokyo.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Maeda
authors.forename: M
authors.initials: M
authors.lastname: Akanuma
authors.forename: Y
authors.initials: Y
authors.lastname: Mitsuno
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: K
authors.initials: K
authors.lastname: Ogura
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Shiratori
authors.forename: M
authors.initials: M
authors.lastname: Omata
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D029721:Drosophila Proteins; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases; D016209:Interleukin-8 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism* / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017354:Point Mutation; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000382:microbiology; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D002518:Ceramides; D016207:Cytokines; D018076:DNA, Complementary; D029721:Drosophila Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases