FR167653, a p38 mitogen-activated protein kinase inhibitor, prevents Helicobacter pylori-induced gastritis in Mongolian gerbils

FR167653 was discovered as a cytokine production inhibitor, but its target molecule has remained unclear. We examined the effect of FR167653 on activi ties of purified protein kinases. FR167653 dose dependently inhibited p38 a lpha mitogen-activated protein kinase activity without affecting the activi ties of other kinases. FR167653 had no effect on cyclooxygenase (COX)-1 or COX-2 activities, whereas SB203580 inhibited them. FR167653 suppressed endo genous p38 kinase activity in interleukin-1-stimulated NRK-F cells. These r esults indicate that FR167653 is a p38 kinase-selective inhibitor without a ffecting COX activity. To evaluate the role of p38 kinase in Helicobacter p ylori gastritis, we therefore examined the effect of FR167653 on H. pylori- induced gastritis in Mongolian gerbils. H. pylori infection activated p38 k inase in the gastric mucosa and caused neutrophil infiltration from 2 and 3 weeks of infection, respectively. At 4 weeks, severe mucosal inflammation with erosive injury was observed. When FR167653 was administered to H. pylo ri-infected gerbils from 2 weeks, both neutrophil infiltration and mucosal injury at 4 weeks were significantly prevented. FR167653 markedly reduced t he H. pylori-induced increase in endogenous p38 kinase activity in the gast ric mucosa, and also significantly inhibited neutrophil chemokine productio n. In contrast, the drug did not affect H. pylori colonization or acid secr etion. FR167653 did not cause any pathological change in the gastric mucosa of normal animals. These results indicate that p38 kinase plays a crucial role in H. pylori-induced gastritis in Mongolian gerbils.