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Regulation of cathepsin X overexpression in H. pylori ‐infected gastric epithelial cells and macrophages
Author(s) -
Krueger Sabine,
Kuester Doerthe,
Bernhardt Anja,
Wex Thomas,
Roessner Albert
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2485
Subject(s) - caga , helicobacter pylori , signal transduction , secretion , gastric mucosa , epithelium , biology , macrophage , microbiology and biotechnology , blot , chemistry , in vitro , stomach , endocrinology , gene , biochemistry , genetics , virulence
Cathepsin X (CTSX) is strongly up‐regulated in Helicobacter pylori ‐infected gastric mucosa and intestinal‐type gastric cancer. The overexpression of CTSX is mediated predominantly by associated macrophages; depends on a functional type IV‐secretion system; and leads to increased migration of gastric epithelial cells. In the present study, we analysed the role of CagA in CTSX overexpression and identified H. pylori ‐induced inflammatory factors and signalling pathways required for stimulating CTSX expression by H. pylori . Gastric epithelial cells were co‐cultured with macrophages in Transwell chambers of 0.4 µm pore size, enabling exchange of fluids but retracting H. pylori . N87 gastric epithelial cells were infected with H. pylori P1 wild‐type strain in the presence of inhibitors for p38, JNK, and ERK1/2 signal transduction pathways. Furthermore, cytokines and growth factors were tested for their regulatory function using inhibitory antibodies, and their gene expression was studied by quantitative RT‐PCRs and western blots. CTSX is strongly up‐regulated at both the mRNA and the protein levels by TNF‐α, IL‐1β, IL‐6, and IL‐8, depending on cell type. All these cytokines were found to be increased by five‐ to ten‐fold in macrophages by H. pylori infection of co‐cultured N87 gastric epithelial cells. In macrophages, H. pylori up‐regulated CTSX via ERK1/2 signalling pathways, and in N87 cells via JNK irrespective of p38 signalling. Our results suggest that H. pylori induced overexpression of CTSX in macrophages and epithelium through specific cytokines that are initiated by CagA‐dependent pathways in a cell type‐dependent manner. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.