Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B4 and inhibition by adenosine A2A receptor engagement.
We report in human neutrophils (PMN) that phospholipase D (PLD) was stimulated by micromolar concentrations of arachidonic acid (AA) and nanomolar concentrations of leukotriene B(4) (LTB(4)), and eicosapentaenoic acid was inactive. The stimulatory effect of AA occurred only when adenosine was eliminated from PMN suspensions or when PMN were incubated with adenosine A(2A) receptor antagonists. The mechanism of AA-induced PLD activation was investigated. The results show that AA- and LTB(4)-induced PLD activation were inhibited by the LTB(4) receptor 1 (BLTR1) antagonist CP 105,696, whereas the LTA(4) hydrolase inhibitor SC57461A and the LT biosynthesis inhibitor MK-0591 inhibited AA- but not LTB(4)-mediated PLD activation. The AA-induced ARF1 and RhoA translocation to PMN membranes was inhibited by CP 105,696 and SC57461A. These results provide evidence of a requirement for an autocrine-stimulatory loop involving LTB(4) and BLTR1 in the translocation of small GTPases to membranes and the activation of PMN PLD by AA.
Grenier
Sonya
S
Canadian Institutes for Health Research Group on the Molecular Mechanisms of Inflammation, Centre de Recherche en Rhumatologie et Immunologie, Québec, Canada.
Flamand
Nicolas
N
Pelletier
Julie
J
Naccache
Paul H
PH
Borgeat
Pierre
P
Bourgoin
Sylvain G
SG
D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology*; D019898:Autocrine Communication / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D001692:Biological Transport; D002264:Carboxylic Acids / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010739:Phospholipase D / Q000378:metabolism*; D021381:Protein Transport; D058915:Purinergic P1 Receptor Antagonists; D011804:Quinolines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D001578:Benzopyrans; D002264:Carboxylic Acids; D007211:Indoles; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D011804:Quinolines; D043705:Receptor, Adenosine A2A; D018102:Receptors, Leukotriene B4; D018047:Receptors, Purinergic P1; C104311:SC 57461; D015091:beta-Alanine; C078266:MK 0591; D007975:Leukotriene B4; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D010739:Phospholipase D; D004851:Epoxide Hydrolases; D020823:ADP-Ribosylation Factor 1; D020742:rhoA GTP-Binding Protein; C043134:leukotriene A4 hydrolase; C089698:CP 105696