title: Agonist-specific cross talk between ERKs and p38(mapk) regulates PGI(2) synthesis in endothelium.
abstract: We have examined the mechanisms regulating prostacyclin (PGI(2)) synthesis after acute exposure of human umbilical vein endothelial cells (HUVEC) to interleukin-1 alpha (IL-1 alpha). IL-1 alpha evoked an early (30 min) release of PGI(2) and [(3)H]arachidonate that was blocked by the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor arachidonyl trifluoromethyl ketone. IL-1 alpha-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2; p42/p44(mapk)) coincided temporally with phosphorylation of cPLA(2)alpha and with the onset of PGI(2) synthesis. The mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, PD-98059 and U-0126, blocked IL-1 alpha-induced ERK activation and partially attenuated cPLA(2)alpha phosphorylation and PGI(2) release, suggesting that ERK-dependent and -independent pathways regulate cPLA(2)alpha phosphorylation. SB-203580 treatment enhanced IL-1 alpha-induced MEK, p42/44(mapk), and cPLA(2)alpha phosphorylation but reduced thrombin-stimulated MEK and p42/44(mapk) activation. IL-1 alpha, but not thrombin, activated Raf-1 as assessed by immune-complex kinase assay, as did SB-203580 alone. These results show that IL-1 alpha causes an acute upregulation of PGI(2) generation in HUVEC, establish a role for the MEK/ERK/cPLA(2)alpha pathway in this early release, and provide evidence for an agonist-specific cross talk between p38(mapk) and p42/44(mapk) that may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, London NW1 0TU, United Kingdom.
authors.forename: R A
authors.initials: RA
authors.lastname: Houliston
authors.forename: J D
authors.initials: JD
authors.lastname: Pearson
authors.forename: C P
authors.initials: CP
authors.lastname: Wheeler-Jones
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D054513:Group IV Phospholipases A2; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D006490:Hemostatics; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; C081565:arachidonyltrifluoromethane; D016718:Arachidonic Acid; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D013917:Thrombin; C093642:SB 203580