Urease Release by Helicobacter pylori Stimulates Macrophage Inducible Nitric Oxide Synthase

Inducible NO synthase (iNOS) expression and production of NO are both up-regulated with Helicobacter pylori infection in vivo and in vitro. We determined whether major pathogenicity proteins released by H. pylori activate iNOS by coculturing macrophages with wild-type or mutant strains deficient in VacA, CagA, picB product, or urease (ureA super(-)). When filters were used to separate H. pylori from macrophages, there was a selective and significant decrease in stimulated iNOS mRNA, protein, and NO sub(2) super(-) production with the ureA super(-) strain compared with wild-type and other mutants. Similarly, macrophage NO sub(2) super(-) generation was increased by H. pylori protein water extracts of all strains except ureA super(-). Recombinant urease stimulated significant increases in macrophage iNOS expression and NO sub(2) super(-) production. Taken together, these findings indicate a new role for the essential H. pylori survival factor, urease, implicating it in NO-dependent mucosal damage and carcinogenesis.