Reciprocal modulation of anti-IgE induced histamine release from human mast cells by A₁ and A(2B) adenosine receptors

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&sub1;, A(2A) , A(2B) and A&sub3;) 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

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&sub1;, A(2A) , A(2B) and A&sub3;) 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

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⁻&sup9;-10⁻&sup7; mol·L⁻¹) and inhibition at higher concentrations (10⁻&sup6;-10⁻&sup4; mol·L⁻¹). The potentiating action was mimicked by A&sub1; AR agonists CCPA and 2'MeCCPA, and inhibited by the A&sub1; AR antagonist PSB36. In contrast, the inhibitory action of adenosine was mimicked by the non-specific A&sub2; 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&sub1; 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&sub1; AR antagonists, but not A(2B) AR antagonists.