Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

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Abstract
1 Engagement of adenosine A2 receptors suppresses several leukocyte functions. In the present study, we examined the effect of adenosine on the inhibition of leukotriene B4 (LTB4) synthesis in heparinized human whole blood, pretreated with lipopolysaccharide (LPS) and tumour necrosis factor α (TNF-α) and stimulated with the chemotactic peptide, N-formyl-Met-Leu-Phe (FMLP). 2 The FMLP-induced synthesis of LTB4 in whole blood pretreated with LPS and TNF-α was dose-dependently inhibited by adenosine analogues in the following order of potency; 5′(N-ethyl)carbox- amidoadenosine (NECA) ≅ CGS 21680 > 2-Cl-adenosine > N6-cyclopentyladenosine (CPA), indicating the involvement of the adenosine A2 receptor subtype. The IC50 values for NECA, CGS 21680, 2-Cl- adenosine, and CPA were 6nM, 9nM, 180nM, and 990 nM, respectively. 3 Dipyridamole, an agent that blocks the cellular uptake of adenosine by red cells and causes its accumulation in plasma, also inhibited the synthesis of LTB4 in LPS and TNF-α-treated whole blood stimulated by FMLP; moreover, this inhibition was reversed upon addition of adenosine deaminase. 4 A highly selective antagonist of the adenosine A2 receptor, 8-(3-chlorostyryl)caffeine (CSC), reversed the inhibition of LTB4 synthesis by 2-Cl-adenosine and dipyridamole in LPS and TNF-α-treated whole blood, stimulated by FMLP. 5 LTB4 synthesis in whole blood originates predominantly from neutrophils and to a lesser extent from monocytes. 2-Cl-adenosine also inhibited the synthesis of LTB4 induced by FMLP in these isolated LPS and TNF-α-treated cells; however, 2-Cl-adenosine was a more potent inhibitor of LTB4 synthesis in neutrophils than monocytes. 6 The present data demonstrate that adenosine, acting through A2 receptors, exerts a potent inhibitory effect on the synthesis of LTB4 and thus contribute to the understanding of its anti-inflammatory properties.

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