Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:FR167653, a p38 mitogen-activated protein kinase inhibitor, prevents Helicobacter pylori-induced gastritis in Mongolian gerbils. 1112 61

Matrix metalloproteinases (MMPs) are a family of endopeptidases implicated in a wide rage of degenerative and inflammatory diseases, including Helicobacter pylori-associated gastritis, and gastric and duodenal ulcer. As gastric mucosal inflammatory responses to H. pylori are characterized by the rise in MMP-9 production, as well as the induction in mitogen-activated protein kinase (MAPK) and Rac1 activation, we investigated the role of Rac1/MAPK in the processes associated with the release of MMP-9. We show that H. pylori LPS-elicited induction in gastric mucosal MMP-9 release is associated with MAPK, ERK and p38 activation, and occurs with the involvement of Rac1 and cytosolic phospholipase A2 (cPLA2). Further, we demonstrate that the LPS-induced MMP-9 release requires ERK-mediated phosphorylation of cPLA2 on Ser(505) that is essential for its membrane localization with Rac1, and that this process necessitates p38 participation. Moreover, we reveal that the activation and membrane translocation of p38 to the Rac1-GTP complex plays a pivotal role in cPLA2-dependent enhancement in MMP-9 release. Hence, our findings provide a strong evidence for the role of ERK/cPLA2 and Rac1/p38/cPLA2 cascade in H. pylori LPS-induced up-regulation in gastric mucosal MMP-9 release.
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PMID:Helicobacter pylori-elicited induction in gastric mucosal matrix metalloproteinase-9 (MMP-9) release involves ERK-dependent cPLA2 activation and its recruitment to the membrane-localized Rac1/p38 complex. 2688 72