Distinct Mechanism of Helicobacter pylori-mediated NF-κB Activation between Gastric Cancer Cells and Monocytic Cells

Abstract

NF-κB 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-κB 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-κB in both cells, isogenic mutant of cagE (ΔcagE) activated it only in THP-1 cells. Supernatant from the wild type culture could activate NF-κB in THP-1 cells but not in MKN45 cells. High density cDNA array analysis revealed that mRNA expression of NF-κB-regulated genes such as interleukin (IL)-8, tumor necrosis factor-α (TNFα), and IL-1β was significantly up-regulated by the wild type in both cells, whereas it was up-regulated by ΔcagE only in THP-1 cells. Experiments using CD14-neutralizing antibody and IL-1 receptor-associated kinase (IRAK) assay showed that both wild type and ΔcagE H. pylori activated NF-κB 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-κB activation and TNFα secretion compared with C3H/HeN mouse macrophage when treated with H. pylori. In conclusion, H. pylori-induced NF-κB 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.