PT  - JOURNAL ARTICLE
AU  - Marc E. Surette
AU  - Eric Krump
AU  - Serge Picard
AU  - Pierre Borgeat
TI  - Activation of Leukotriene Synthesis in Human Neutrophils by Exogenous Arachidonic Acid: Inhibition by Adenosine A<sub>2a</sub> Receptor Agonists and Crucial Role of Autocrine Activation by Leukotriene B<sub>4</sub>
AID  - 10.1124/mol.56.5.1055
DP  - 1999 Nov 01
TA  - Molecular Pharmacology
PG  - 1055--1062
VI  - 56
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/56/5/1055.short
4100  - http://molpharm.aspetjournals.org/content/56/5/1055.full
SO  - Mol Pharmacol1999 Nov 01; 56
AB  - We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is the consequence of A2a receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when adenosine is eliminated from PMN suspensions by the addition of adenosine deaminase, or when cells are incubated with adenosine A2a receptor antagonists, important quantities (40–80 pmol/106 cells) of 5-lipoxygenase products are synthesized by PMN incubated with 1 to 5 μM exogenous AA. The selective A2a receptor agonist CGS21680 was a very potent inhibitor of the AA-induced leukotriene (LT) synthesis, showing an IC50 of ∼1 nM. The mechanism of AA-induced stimulation of LT synthesis observed in the absence of extracellular adenosine was investigated. In adenosine deaminase-treated PMN, exogenous AA induced Ca2+ mobilization and the translocation of 5-lipoxygenase to nuclear structures. A time lag of 20 to 60 s (variable between PMN preparations) was observed consistently between the addition of AA and the elevation of intracellular Ca2+ concentration (and LT synthesis), indicating that AA itself did not trigger the Ca2+ mobilization in PMN. This AA-induced Ca2+mobilization, as well as the corresponding 5-lipoxygenase translocation and stimulation of LT synthesis, was blocked efficiently by the LT synthesis inhibitor MK0591, the LTB4 receptor antagonists CP105696 and LY223982, and the LTA4 hydrolase inhibitor SC57461A. These data demonstrate that AA is a highly potent and effective activator of LT synthesis and acts through a mechanism that requires an autocrine stimulatory loop by LTB4.