HELICOBACTER-PYLORI UP-REGULATES EXPRESSION OF EPIDERMAL GROWTH FACTOR-RELATED PEPTIDES, BUT INHIBITS THEIR PROLIFERATIVE EFFECT IN MKN-28 GASTRIC-MUCOSAL CELLS

Acute exposure to Helicobacter pylori causes cell damage and impairs t he processes of cell migration and proliferation in cultured gastric m ucosal cells in vitro. EGF-related growth factors play a major role in protecting gastric mucosa against injury, and are involved in the pro cess of gastric mucosal healing. We therefore studied the acute effect of H. pylori on expression of EGF-related growth factors and the prol iferative response to these factors in gastric mucosal cells (MKN 28) derived from gastric adenocarcinoma. Exposure of MKN 28 cells to H. py lori suspensions or broth culture filtrates upregulated mRNA expressio n of amphiregulin (AR) and heparin-bindhng EGF-like growth actor (HB-E GF), but not TGF alpha. This effect was specifically related to H. pyl ori since it was not observed with E. coli, and was independent of Vac A, CagA, PicA, PicB, or ammonia. Moreover, H. pylori broth culture fil trates stimulated extracellular release of AR and HB-EGF protein by MK N 28 cells. AR and HB-EGF dose-dependently and significantly stimulate d proliferation of MKN 28 cells in the absence of H. pylori filtrate, but had no effect in the presence of H. pylori broth culture filtrates . Inhibition of AR- or HB-EGF-induced stimulation of cell growth was n ot mediated by downregulation of the EGF receptor since EGF receptor p rotein levels, EGF binding affinity, number of specific binding sites for EGF, or HB-EGF- or AR-dependent tyrosine phosphorylation of the EG F receptor were not significantly altered by incubation with H. pylori broth culture filtrates. Increased expression of AR and HB-EGF were m ediated by an H. pylori factor > 12 kD in size, whereas antiproliferat ive effects were mediated, by both VacA and a factor < 12 kD in size. We conclude that H. pylori increases mucosal generation of EGF-related peptides, but in this acute experimental model, this event is not abl e to counter-act the inhibitory effect of H. pylori on cell growth. Th e inhibitory effect of H. pylori on the reparative events mediated by EGF-related growth factors might play a role in the pathogenesis of H. pylori-induced gastroduodenal injury.