Class II MHC molecules on gastric epithelial cells act as receptors for Helicobacter pylori urease and signal apoptosis of the epithelium

Helicobacter pylori (Hp) damages the gastric epithelium and may lead to peptic ulcer and cancer. We have shown that Hp binds to class IIMHC on gastric epithelial cells and signals apoptosis. However, the Hp proteins that bind to class II MHC and trigger apoptosis are not known. Since urease is a major Hp product that stimulates cytokine secretion by class II MHC⁺ cells, we hypothesized that apoptosis in gastric epithelial cells is signaled through class II MHC molecules subsequent to urease binding. To determine the interaction of urease with class II MHC, urease-coated beads were incubated with [³⁵S] labeled proteins from gastric epithelial cell lines (Kato III, N87 and AGS) as well as HLA-DR1-transfected (1D12) COS-1 cells. Bound proteins were eluted and electrophoresis analysis revealed class II MHC among the eluted proteins. IFN-γ increased the binding of urease to Kato III and N87, which are class II MHC^-, but not to AGS, which is class IIMHC. Urease binding was blocked by anti-class MHC mAb. Also, urease bound only to HLA-DR1-transfected COS-1 (1D12) cells but not to COS-1 cells. To confirm the interaction of urease with class II MHC, 96-well plates were coated with urease, to which binding affinity-purified class II MHC from [³⁵S] labeled gastric epithelial cells were added. Gel electrophoresis of the bound material confirmed that class II MHC α and β chains bound to the wells coated with urease but not to the control wells. Urease induced apoptosis in class II MHC^-, but not in class II MHC^- cell lines as determined by ELISA and this apoptosis was blocked by Fab fragments from anti-class II MHC. These observations uncover a new role for H. pylori urease in associated diseases as well as a novel ligand for class II MHC.