Activation of Leukotriene Synthesis in Human Neutrophils by Exogenous Arachidonic Acid: Inhibition by Adenosine A2aReceptor Agonists and Crucial Role of Autocrine Activation by Leukotriene B4

• DOI: 10.1124/mol.56.5.1055
• Publication Date: 2018-01-08T20:37:23Z
• Authors: Marc E. Surette; Eric Krump; Serge Picard; Pierre Borgeat
• Keywords: Cell Nucleus; Epoxide Hydrolases; 0301 basic medicine; Leukotrienes; 0303 health sciences; Adenosine; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Indoles; Carboxylic Acids; Biological Transport; In Vitro Techniques; Adrenergic Agonists; Leukotriene B4; 3. Good health; Autocrine Communication; Kinetics; 03 medical and health sciences; Eicosapentaenoic Acid; Humans; Leukotriene Antagonists; Benzopyrans; Calcium; Biotransformation

We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is consequence A_2a receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when eliminated from PMN suspensions addition deaminase, or cells are incubated with antagonists, important quantities (40–80 pmol/10⁶ cells) 5-lipoxygenase products synthesized 1 5 μM exogenous AA. The selective agonist CGS21680 was a very potent inhibitor AA-induced leukotriene (LT) synthesis, showing an IC₅₀ ∼1 nM. mechanism stimulation LT synthesis observed absence extracellular investigated. In deaminase-treated PMN, AA induced Ca²⁺ mobilization and translocation nuclear structures. A time lag 20 60 s (variable between preparations) consistently elevation intracellular concentration (and synthesis), indicating itself did not trigger PMN. This Ca²⁺mobilization, as well corresponding blocked MK0591, LTB₄ antagonists CP105696 LY223982, LTA₄ hydrolase SC57461A. These data demonstrate highly effective activator acts through requires autocrine stimulatory loop LTB₄.