TNF-α-inducing protein, a carcinogenic factor secreted from H. pylori, enters gastric cancer cells

TNF-α inducing protein (Tipα) is secreted from Helicobacter pylori (H. pylori): it is a potent inducer of TNF-α and chemokine genes, mediated through NF-κB activation, and it also induces tumor-promoting activity in Bhas 42 cells. To investigate the carcinogenic mechanisms of H. pylori with Tipα, we first examined how Tipα acts on gastric epithelial cells. We found that fluorescent-Tipα specifically bound to, and then entered, the cells in a dose- and temperature-dependent manner, whereas deletion mutant of Tipα (del-Tipα), an inactive form, neither bound to nor entered the cells, suggesting the presence of a specific binding molecule. Mutagenesis analysis of Tipα revealed that a dimer formation of Tipα with a disulfide bond is required for both specific binding and induction of TNF-α gene expression. A confocal laser scanning microscope revealed some Tipα in the nuclei, but del-Tipα was not present, which indicated that an active form of Tipα can penetrate the nucleus and may be involved in the induction of TNF-α gene expression. Examination of Tipα production and secretion in 28 clinical isolates revealed that H. pylori obtained from gastric cancer patients secreted Tipα in significantly higher amounts than did H. pylori from patients with chronic gastritis, suggesting that Tipα is an essential factor in H. pylori inflammation and cancer microenvironment in the human stomach. Tipα is thus a new carcinogenic factor of H. pylori that can enter the nucleus through a specific binding molecule, and its mechanism of action is completely different from that of CagA. © 2008 Wiley-Liss, Inc.