New tumor necrosis factor-α-inducing protein released from Helicobacter pylori for gastric cancer progression

Purpose: To investigate the association between Helicobacter pylori infection and its inflammatory reaction in gastritis, gastric ulcer, and gastric cancer, a new tumor necrosis factor-alpha (TNF-alpha)-inducing protein of H. pylori was studied. Methods: The HP0596 gene of H. pylori was identified as the TNF-alpha-inducing protein (Tip alpha) gene from genome sequence of H. pylori strain 26695. Using recombinant Tip alpha (rTip alpha) and deleted Tip alpha (rdel-Tip alpha) proteins, the latter of which lacks six amino acids containing two cysteines in the N-terminal domain, we examined their activities in TNF-alpha gene expression and NF-kappa B activation in both Bhas 42 (v-Hras transfected BALB/3T3) cells and mouse gastric epithelial cell line MGT-40, and in vitro transformation of Bhas 42 cells. Results: Tipa protein as a homodimer form ( 38 kDa) was found in both extracts and culture medium of various H. pylori strains. rTipa significantly induced TNF-alpha gene expression and NF-kappa B activation in both Bhas 42 cells and MGT-40, and induced in vitro transformation of Bhas 42 cells. However, rdel-Tip alpha did not. Treatment with MG-132, a proteasome inhibitor, inhibited translocation of NF-kappa B p65, and abrogated TNF-alpha induction induced by Tipa protein. Conclusion: Tipa is a new carcinogenic factor released from H. pylori mediated through NF-kappa B activation.