ADENOSINE A(2B) RECEPTORS EVOKE INTERLEUKIN-8 SECRETION IN HUMAN MAST-CELLS - AN ENPROFYLLINE-SENSITIVE MECHANISM WITH IMPLICATIONS FOR ASTHMA

Adenosine potentiates mast cell activation, but the receptor type and molecular mechanisms involved have not been defined. We, therefore, investigated the effects of adenosine on the human mast cell line HMC-1. Both the A(2a) selective agonist CGS21680 and the A(2a)/A(2b) nonselective agonist 5'N-ethylcarboxamidoadenosine (NECA) increased cAMP, but NECA was fourfold more efficacious and had a Hill coefficient of 0.55, suggesting the presence of both A(2a) and A(2b) receptors, NECA 10 mu M evoked IL-8 release from HMC-1, but CGS21680 10 mu M had no effect, In separate studies we found that enprofylline, an antiasthmatic previously thought to lack adenosine antagonistic properties, is as effective as theophylline as an antagonist of A(2b) receptors at concentrations achieved clinically, Both theophylline and enprofylline 300 mu M completely blocked the release of IL-8 by NECA, NECA, but not CGS21680, increases inositol phosphate formation and intracellular calcium mobilization through a cholera and pertussis toxin-insensitive mechanism, In conclusion, both A(2a) and A(2b) receptors are present in HMC-1 cells and are coupled to adenylate cyclase. In addition, A(2b) receptors are coupled to phospholipase C and evoke IL-8 release, This effect is blocked by theophylline and enprofylline, raising the possibility that this mechanism contributes to their antiasthmatic effects.