Cytosolic phospholipase A2 activation in Helicobacter pylori lipopolysaccharide-induced interference with gastric mucin synthesis.
Release of arachidonic acid from membrane glycerophospholipids by cytosolic phospholipase A2 (cPLA2) is a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. Here, we report on the role of cPLA2 in the disturbances in gastric mucin synthesis evoked by the LPS of H. pylori, a bacterium identified as a primary cause of gastric disease. Using rat gastric mucosal cells, we show that H. pylori LPS detrimental effect on gastric mucin synthesis, associated with up-regulation in PAF and endothelin-1 (ET-1) generation, was subject to suppression by a specific inhibitor of cPLA2, MAFP. Moreover, the LPS-induced changes in mucin synthesis and ET-1 generation were countered by PAF receptor antagonist, BN52020. The impedance by PAF antagonist of the LPS-induced reduction in mucin synthesis was countered by wortmannin, an inhibitor of PI3K, as well as by ERK inhibitor, PD98059. The blockade of ERK caused also inhibition of the LPS-induced cPLA2 activation and amplification in the impedance capacity of PAF antagonist on the LPS-induced ET-1 generation, while the inhibitor of PI3K had no effect. Our findings are the first to demonstrate that the detrimental consequences of H. pylori LPS on gastric mucin synthesis involve ERK-dependent cPLA2 activation that leads to up-regulation in PAF generation and ET-1 production.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D019332:Endothelin-1 / Q000096:biosynthesis; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008954:Models, Biological; D009077:Mucins / Q000096:biosynthesis*; D063065:Organophosphonates / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin
D000730:Androstadienes; D001095:Arachidonic Acids; D019332:Endothelin-1; D005419:Flavonoids; D046934:Ginkgolides; D007783:Lactones; D008070:Lipopolysaccharides; D009077:Mucins; D063065:Organophosphonates; D010713:Phosphatidylcholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010972:Platelet Activating Factor; C442865:lipopolysaccharide, Helicobacter pylori; C104810:methyl arachidonylfluorophosphonate; C081346:1-(hexylthio)-2-(hexanoylamino)-1,2-dideoxy-sn-glycero-3-phosphocholine; D048049:Extracellular Signal-Regulated MAP Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C477042:ginkgolide A; D000077191:Wortmannin