Microreview Molecular response of gastric epithelial cells to Helicobacter pylori -induced cell damage Raffaele Zarrilli, 1 * Vittorio Ricci 2² and Marco Romano 3 1 Dipartimento di Biologia e Patologia Cellulare e Molecolare `L. Califano', Centro di Endocrinologia ed Oncologia Sperimentale `G. Salvatore' del Consiglio Nazionale delle Ricerche, Universita Á `Federico II', Via S. Pansini 5, Naples, 80131 Italy. 2 Istituto di Fisiologia Umana, Universita Á di Pavia, Pavia, 27100 Italy. 3 Dipartimento di Internistica Clinica e Sperimentale ± Divisione di Gastroenterologia, II Ateneo di Napoli, Naples, 80131 Italy. Summary Infection with the Gram-negative bacterium Helico- bacter pylori leads to different clinical and pathologi- cal outcomes in humans, including chronic gastritis, peptic ulcer disease and adenocarcinoma of the stomach. H. pylori -induced damage to gastric muco- sal cells is controlled by bacterial virulence factors encoded by genes of the cag pathogenicity island, which trigger the in¯ammatory response of the host through the activation of nuclear factor kB-dependent gene transcription. Also, H. pylori infection impairs the processes of gastric mucosal healing through inhibition of epidermal growth factor receptor-depen- dent signal transduction pathways and induction of apoptosis. H. pylori infection may in¯uence the pro- gression from chronic gastritis to gastric adenocarci- noma by stimulating cell proliferation and growth factor expression, inhibiting apoptosis and increas- ing the DNA mutation rate of infected gastric mucosa. Introduction Helicobacter pylori is a Gram-negative, microaerophilic, S-shaped bacterium that is free-living in the mucous layer of the human stomach; only a small proportion attaches to gastric epithelial cells without invading them. Colonization of the stomach by H. pylori induces in®ltration of the lamina propria and epithelium with immunocytes and in¯ammatory cells, a condition referred to as chronic gastritis or chronic active gastritis. During the years or dec- ades that follow the initial infection, chronic gastritis may remain asymptomatic or may evolve into more severe dis- eases, such as peptic ulcer or atrophic gastritis. In addition, infection with H. pylori increases the risk of developing gastric adenocarcinoma and mucosa-associated lym- phoid tissue lymphoma (Blaser and Parsonnet, 1994; Dunn et al., 1997; Covacci et al., 1999). This microreview focuses on the molecular mechanisms of gastric epithelial cell response to H. pylori -induced cell damage and on experimental evidence supporting a role for H. pylori in gastric carcinogenesis. For an in-depth dis- cussion of other aspects of H. pylori -induced gastroduo- denal disease and virulence factors, the reader is referred to earlier reviews (Blaser and Parsonnet, 1994; Dunn et al., 1997; Covacci et al., 1999). Mechanisms of H. pylori -induced cell damage H. pylori -induced gastroduodenal disease depends on the in¯ammatory response of the host and on the production of speci®c virulence factors that cause damage to gastric epithelial cells and disruption of the gastric mucosal bar- rier, such as urease, responsible for ammonia generation, and the vacuolating cytotoxin VacA (Dunn et al., 1997; Covacci et al., 1999). Cytokines contribute to mucosal damage, either directly or indirectly, by mediating in¯ammatory response to H. pylori. The gastric mucosal levels of the proin¯ammatory cytokines interleukin 1b (IL-1b), IL-6, IL-8 and tumour necrosis factor ( TNF-a) are increased in H. pylori -infected subjects (Wilson et al., 1998). The local cytokine response to H. pylori infection is of the Th1 type, as interferon gamma (IFN- g), but not IL-4, is upregulated (Lindholm et al., 1998). Variation in the ability of H. pylori strains to trig- ger chemokines from gastric epithelium has been linked to the presence of genes in the cag (cytotoxin-associated gene) pathogenicity island (PAI) (Covacci et al., 1999). The cag PAI is a 40 kb chromosomal DNA insertion at Cellular Microbiology (1999) 1(2), 93±99 Q 1999 Blackwell Science Ltd Received 1 July, 1999; revised 20 August, 1999; accepted 24 August, 1999. ²Present address: INSERM U452, Faculte  de Me  dicine, 28 Avenue de Valombrose, 06107 Nice Cedex, France. *For correspon- dence. E-mail rafzarri@cds.unina.it; Fax (39) 81 770 3285.