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 activities of purified protein kinases. FR167653 dose dependently inhibited p38alpha mitogen-activated protein kinase activity without affecting the activities of other kinases. FR167653 had no effect on cyclooxygenase (COX)-1 or COX-2 activities, whereas SB203580 inhibited them. FR167653 suppressed endogenous p38 kinase activity in interleukin-1-stimulated NRK-F cells. These results indicate that FR167653 is a p38 kinase-selective inhibitor without affecting COX activity. To evaluate the role of p38 kinase in Helicobacter pylori gastritis, we therefore examined the effect of FR167653 on H. pylori-induced gastritis in Mongolian gerbils. H. pylori infection activated p38 kinase 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. pylori-infected gerbils from 2 weeks, both neutrophil infiltration and mucosal injury at 4 weeks were significantly prevented. FR167653 markedly reduced the H. pylori-induced increase in endogenous p38 kinase activity in the gastric mucosa, and also significantly inhibited neutrophil chemokine production. In contrast, the drug did not affect H. pylori colonization or acid secretion. 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.
Takahashi
S
S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Keto
Y
Y
Fujita
T
T
Uchiyama
T
T
Yamamoto
A
A
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005753:Gastric Mucosa / Q000201:enzymology / Q000382:microbiology; D005756:Gastritis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000150:complications* / Q000201:enzymology; D016480:Helicobacter pylori; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; C104334:FR 167653; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D011725:Pyridines; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases