Differential regulation of human basophil and lung mast cell function by adenosine

Adenosine was found to modulate the activity of the human basophil and lung mast cell (HLMC) differently. In the basophil, adenosine inhibited the anti-IgE stimulated release of histamine and leukotriene C₄ (LTC₄) and increased total cell cyclic AMP (cAMP) levels. Substituted adenosine analogs had a rank order potency of: N-ethylcarboxamideadenosine (NECA) > 2-chloroadenosine > R-phenylisopropyladenosine for the inhibition of immunoglobulin E-triggered mediator release from the basophil and increases in cAMP levels. The adenosine receptor antagonist, 8-phenyltheophylline, antagonized both the NECA-induced inhibition of mediator release and elevations in cyclic nucleotide. The purinergic transport inhibitor, dipyridamole, reversed the inhibition by adenosine of histamine release but not LTC₄ generation, suggesting that these two actions are mechanistically separable. Dipyridamole failed to modify the adenosine-induced elevation in cAMP. In contrast to the findings in the basophil, the response to adenosine in the HLMC was biphasic in nature. Thus, at low concentrations of the nucleoside, adenosine potentiated the release of histamine and LTC₄ from immunologically activated HLMC, whereas at higher concentrations a counteractive inhibitory process was observed. Analogs of adenosine had the same effects on HLMC; NECA was more potent than R-phenylisopropyladenosine for both the potentiating and inhibitory components of the biphasic response. Low concentrations of adenosine analogs, which potentiated secretion, initiated modest elevations in cAMP levels, whereas higher concentrations, which inhibited secretion, significantly augmented cAMP levels. Although R-phenylisopropyladenosine was almost as potent as NECA at elevating cAMP in HLMC, it was not as efficacious. The NECA-induced modulation of HLMC mediator release and elevations in cAMP were antagonized by 8-phenyltheophylline. In total, these results suggest that the basophil possesses an alpha₂ receptor but that adenosine, as well as interacting with this receptor, also exerts intracellular, cAMP-independent effects, which are involved in countering the release of histamine but not LTC₄. In the HLMC, rationalizing the experimental data to adenosine receptor subtypes proves more problematical. It is suggested that the inhibitory arm of the biphasic response is mediated through activation of an adenylate cyclase-coupled atypical alpha₂ receptor. Either the same receptor coupled to an effector system other than adenylate cyclase or a distinct and previously uncharacterized receptor may mediate the enhancement of secretion.