Experimental evidence demonstrated that LPS functions as a TLR-2

ligand by signaling through pathways involving MyD88, IRAK1, IRAK4, TNFR-associated factor 6, IκB kinase-β, and IκBα [48]. Infection of gastric epithelial cells was associated with the decreased expression of signaling factor tribbles-3 (TRIB3), and knockdown of TRIB3 and C/EBP homologous protein enhanced TLR2-mediated NF-κB activation and chemokine induction ABT-199 mw by LPS. Thus, modulation of TRIB3 may be an important mechanism during H. pylori-associated pathogenesis downstream of TLR2 [48]. In addition, using two colon carcinoma cell lines, it was observed that LPS upregulates the expression of inducible nitric oxide (NO), demonstrating its ability to interfere with the DNA repair machinery and increasing risk of genotoxic

www.selleckchem.com/products/nutlin-3a.html effects [49]. Finally, LPS from H. pylori increased the paracellular permeability of cultured gastric cells [50]. Such an effect in vivo would have an important impact on epithelial barrier functions and pathology. H. pylori continuously buds-off outer membrane vesicles (OMVs) from its surface. Purified OMVs revealed their major protein and phospholipid components and some virulence factors [51]. Additional functional and biochemical analyses focused on BabA and SabA adhesins and their respective interactions with the gastric epithelium. Thus, OMVs carry effector-promoting properties which may be important for disease development [51]. However, the mechanism of OMV uptake in host cells is poorly understood. Using inhibitors and mutants, a new report has shown that VacA enhances the association of OMVs with cells and that clathrin-mediated endocytosis is involved, while vesicle internalization

did not require cholesterol in this study [52]. γ-Glutamyl transpeptidase (GGT) has been reported as a pathogenicity factor associated with H. pylori colonization and cell apoptosis. A new study showed that purified GGT inhibits the growth of AGS cells and that caspase-3 inhibitors effectively blocked GGT-induced apoptosis [53]. Cell cycle analysis showed G1 phase arrest and apoptosis following GGT treatment, and this was associated with down-regulation of cyclin-E, cyclin-A, Cdk-4, and Cdk-6 and the upregulation Aspartate of the Cdk inhibitors p27 and p21 [53]. In addition, recombinant GGT, infection with wild-type but not isogenic GGT mutants generated H2O2 in primary gastric epithelial and AGS cells, resulting in the activation of NF-κB and up-regulation of IL-8 [54]. The clinical importance was shown by significantly higher GGT activity in strains obtained from patients with peptic ulcer disease (PUD) than isolates from nonulcer dyspepsia [54]. Another pathogenicity-associated factor is the duodenal ulcer-promoting gene A (dupA). The dupA locus of 34 strains was sequenced. Most dupA alleles were longer (1884 bp; dupA1) than previously described, although some had truncated versions (dupA2) [55].