The PGE2-induced inhibition of the PLD activation pathway stimulated by fMLP in human neutrophils is mediated by PKA at the PI3-Kγ level
| Autor: | Danielle Harbour, Chantal Burelout, Sylvain G. Bourgoin, Nathalie Thibault, Paul H. Naccache |
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| Rok vydání: | 2007 |
| Předmět: |
Neutrophils
Leukotriene B4 Prostaglandin E2 receptor Biochemistry Dinoprostone Phosphatidylinositol 3-Kinases chemistry.chemical_compound Phospholipase D Class Ib Phosphatidylinositol 3-Kinase Humans Receptors Prostaglandin E Phosphorylation Cells Cultured Protein kinase C Pharmacology Superoxide Tyrosine phosphorylation Chemotaxis Receptors Prostaglandin E EP2 Subtype Cyclic AMP-Dependent Protein Kinases Cell biology Enzyme Activation Isoenzymes N-Formylmethionine Leucyl-Phenylalanine chemistry Calcium lipids (amino acids peptides and proteins) Signal transduction |
| Zdroj: | Biochemical Pharmacology. 74:730-741 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2007.06.013 |
| Popis: | Prostaglandin E2 (PGE2), an eicosanoid that modulates inflammation, inhibits several chemoattractant-elicited functions in neutrophils such as chemotaxis, production of superoxide anions, adhesion, secretion of cytotoxic enzymes and synthesis of leukotriene B4. We previously reported that PGE2 inhibits the fMLP signaling pathway that leads to PLD activation through suppression of PI3-Kgamma activity and the decreased recruitment to membranes of PLD activation factors, PKC, Rho and Arf-GTPases. This effect is mediated via the EP2 receptors known to raise cAMP in cells. The inhibition of most fMLP-induced functional responses by PGE2 via EP2 receptors is mediated by PKA, except the chemotactic response. We have investigated the role of PKA in the EP2-mediated inhibition of the PLD activation pathway. H-89, a selective PKA pharmacological inhibitor suppressed the inhibitory effects of PGE2 at all stages of the PLD pathway activated by fMLP, i.e. PLD activity, translocation to membranes of PKCalpha, Rho and Arf-GTPases, calcium influx, tyrosine phosphorylation of proteins and finally translocation of p110gamma catalytic subunit of PI3-K to membranes. However, neither PLD nor PI3-Kgamma was substrate of PKA. These data provide evidence that PGE2-stimulated PKA activity regulates the PLD pathway stimulated by fMLP at the level of PI3-Kgamma and that the inhibition of PI3-Kgamma activation by PKA is a complex mechanism that remains to be completely elucidated. |
| Databáze: | OpenAIRE |
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