Cutting Edge: Urease Release by Helicobacter pylori Stimulates Macrophage Inducible Nitric Oxide Synthase

Abstract

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−). When filters were used to separate H. pylori from macrophages, there was a selective and significant decrease in stimulated iNOS mRNA, protein, and NO2− production with the ureA− strain compared with wild-type and other mutants. Similarly, macrophage NO2− generation was increased by H. pylori protein water extracts of all strains except ureA−. Recombinant urease stimulated significant increases in macrophage iNOS expression and NO2− 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.

Helicobacter pylori-induced Macrophage Apoptosis Requires Activation of Ornithine Decarboxylase by c-Myc

“…2 A related question is whether specific bacterial factors derived from H. pylori play a role in the induction of macrophage apoptosis and whether these factors work through the c-Myc/ ODC pathway. Notably, we have reported that H. pylori LPS is not a significant activator of macrophages (4) but that urease, a major protein product of H. pylori required for colonization of the organism in vivo, is a major inducing factor for inducible NO synthase in macrophages (6). Along these lines, we have found that urease-deficient mutant strains of H. pylori have attenuated ability to induce c-Myc, ODC, and apoptosis, and recombinant urease activates each of these pathways.…”

“…Intriguingly, there is a vigorous gastric mucosal immune response, but this fails to eradicate the organism. H. pylori infection induces a chronic lymphocytic response and an innate immune response in neutrophils, monocytes, and macrophages (2)(3)(4)(5)(6)(7)(8). We have reported several strategies by which the bacterium can avoid host innate immunity by altering macrophage responses to the organism.…”

“…Although H. pylori is a noninvasive pathogen, it can disrupt epithelial integrity, and its antigens are present in the lamina propria (3). H. pylori can induce innate immune response genes and cause apoptosis in macrophages even when separated by filter supports or when water extracts are used (5,6). …”

Helicobacter pylori moves through mucus by reducing mucin viscoelasticity

“…It is well known however, that H. pylori, which is a neutralophile, is able to survive by producing large amounts of the enzyme urease, which catalyzes hydrolysis of urea present in the stomach to yield NH 3 and CO 2 , thus elevating the pH to neutral as necessary for survival (6). It is generally accepted that urea hydrolysis is accomplished by uptake of urea through a proton-gated channel with hydrolysis taking place inside the bacterium and creating a thin neutral layer around the outer surface of the cell (7), although other studies indicate that this crucial enzyme exists on the cell surface (8)(9)(10), or that it is secreted or released (11,12). In addition to its ability to produce urease to elevate pH of its environment, H. pylori further protects itself by swimming through the protective layer of gastric mucus in the stomach and attaching to the epithelial cells beneath, where it can cause inflammation over the course of lifelong infection.…”

Helicobacter pylori – Not Only a Gastric Pathogene?

“…pylori i s a d e c l a r e d t y p e I c a r c i n o g e n ( I ARC, 1994 (Boncristiano et al 2003), 3. H. pylori can induce cell proliferation by increasing levels of several cytokines and regulatory molecules, which are involved in tumour formation and cell transformation (Konturek et al 1997;Sakaguchi et al 1999;Keates et al 2001;Gobert et al 2002;Schiemann et al 2002;Wang et al 2002). Current information about regulation mechanism of epithelial tissue by cytokines and regulatory molecules focus an interest mainly on Epithelial Growth Factor (EGF), Transforming Growth Factor (TGF) and NO synthases (NOS) (Gallo et al 1998;Rubin Grandis et al 1998;Sakaguchi et al 1999;Gobert et al 2002;Schiemann et al 2002).…”