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(Journal of Leukocyte Biology. 2003;73:530-539.)
© 2003 by Society for Leukocyte Biology

Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B₄ and inhibition by adenosine A_2A receptor engagement

Sonya Grenier^*, Nicolas Flamand^*, Julie Pelletier^*, Paul H. Naccache^*,, Pierre Borgeat^*, and Sylvain G. Bourgoin^*,

^* Canadian Institutes for Health Research Group on the Molecular Mechanisms of Inflammation, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ (CHUL) et Départements
d’Anatomie-Physiologie et de
Médecine, Faculté de Médecine, Université Laval, Québec, Canada

Correspondence: Sylvain G. Bourgoin, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ (CHUL), Local T1-49, 2705 Boulevard Laurier, Québec, Qc, Canada, G1V 4G2. E-mail: sylvain.bourgoin{at}crchul.ulaval.ca

We report in human neutrophils (PMN) that phospholipase D (PLD) was stimulated by micromolar concentrations of arachidonic acid (AA) and nanomolar concentrations of leukotriene B₄ (LTB₄), 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 LTB₄-induced PLD activation were inhibited by the LTB₄ receptor 1 (BLTR1) antagonist CP 105,696, whereas the LTA₄ hydrolase inhibitor SC57461A and the LT biosynthesis inhibitor MK-0591 inhibited AA- but not LTB₄-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 LTB₄ and BLTR1 in the translocation of small GTPases to membranes and the activation of PMN PLD by AA.

Key Words: phospholipase A₂ • 5-lipoxygenase • chemotaxis • inflammation • LTB₄ receptors • adenosine deaminase • adenosine receptors • CGS-15943 • CGS-21680 • chlorostyryl caffeine

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