Reciprocal modulation of anti-IgE induced histamine release from human mast cells by A 1 and A 2B adenosine receptors

Abstract

BACKGROUND AND PURPOSE Adenosine is believed to participate in the pathological development of asthma through a mast cell-dependent mechanism. Our study aimed to pharmacologically characterize the functions of adenosine receptor (AR) subtypes (A 1, A 2A, A 2B and A 3) in primary human cultured mast cells (HCMC). EXPERIMENTAL APPROACH HCMC were derived from progenitor stem cells in buffy coat and the effects of adenosine receptor ligands on basal and IgE-dependent histamine release were evaluated. KEY RESULTS Adenosine and analogues alone did not induce HCMC degranulation. When HCMC were activated by anti-IgE after 10 min pre-incubation with adenosine, a biphasic effect on histamine release was observed with enhancement of HCMC activation at low concentrations of adenosine (10 -9-10 -7 mol·L -1) and inhibition at higher concentrations (10 -6-10 -4 mol·L -1). The potentiating action was mimicked by A 1 AR agonists CCPA and 2'MeCCPA, and inhibited by the A 1 AR antagonist PSB36. In contrast, the inhibitory action of adenosine was mimicked by the non-specific A 2 AR agonist CV1808 and attenuated by A 2B AR antagonists PSB1115 and MRS1760. The non-selective AR antagonist CGS15943 attenuated both the potentiating and inhibitory actions. CONCLUSIONS AND IMPLICATIONS We have defined for the first time the contribution of A 1 and A 2B ARs, respectively, to the potentiating and inhibitory action of adenosine on human mast cell activation. With reference to the current trend of developing novel anti-asthmatic agents from AR ligands, our results suggest that inhibition of human mast cell activation would be a mechanism for A 1 AR antagonists, but not A 2B AR antagonists. © 2011 The British Pharmacological Society.