Abstract
Insufficient arachidonic acid availability limits the biosynthesis of leukotriene B4 (LTB4) in polymorphonuclear leukocytes (PMN) stimulated with soluble agonists. We report that endogenous adenosine (Ado) present in human PMN suspensions suppresses LTB4 biosynthesis induced by platelet-activating factor (PAF). The blockade of the effects of Ado with an antagonist, theophylline, during the incubation of PMN resulted in significant enhancement of arachidonic acid release and LTB4 biosynthesis upon PAF stimulation. The enhancement of LTB4 biosynthesis in theophylline-treated PMN was reversed upon addition of exogenous Ado and analogues of Ado; 5’(N-ethyl)caboxamidoadenosine (IC50= 6 nM) was more potent than Ado (IC50 = 60 nM) which was more potent than N6-cyclopentyladenosine (IC50 = 330 nM) in inhibiting LTB4 biosynthesis, a pharmacological profile which is consistent with the involvement of the Ado A2 receptor type. The mechanism of inhibition of arachidonic acid release by Ado was investigated. Immunoblot analysis of cytosolic phospholipase A2 (cPLA2) in PMN fractions demonstrated that theophylline failed to further increase the translocation of the enzyme to particulate fractions (12,000 x g and 180,000 x g pellets) upon PAF stimulation. Moreover, the stimulation of intact PMN with PAF caused a decreased electrophoretic mobility of the cPLA2 and the presence of theophylline did not alter this mobility shift. Together, these results demonstrate that elevated endogenous Ado, acting through A2 receptors, suppresses arachidonic acid release and LTB4 biosynthesis induced by PAF. These data provide an explanation for the relative inability of soluble agonists to trigger leukotriene biosynthesis in human PMN suspensions and support the concept that Ado, by suppressing PMN functions, acts as a physiological anti-inflammatory agent.
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Krump, E., Borgeat, P. (1999). Adenosine. In: Nigam, S., Pace-Asciak, C.R. (eds) Lipoxygenases and their Metabolites. Advances in Experimental Medicine and Biology, vol 447. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4861-4_10
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DOI: https://doi.org/10.1007/978-1-4615-4861-4_10
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