Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A(2B) receptor activation

The effects of adenosine on neutrophil (polymorphonuclear neutrophils; PMN) -directed changes in vascular permeability are poorly characterized. This s tudy investigated whether adenosine modulates activated PMN vascular endoth elial growth factor (vascular permeability factor; VEGF) release and transe ndothelial migration. PMN activated with tumour necrosis factor-alpha (TNF- alpha, 10 ng/mL) were incubated with adenosine and its receptor-specific an alogues. Culture supernatants were assayed for VEGF. PMN transendothelial m igration across human umbilical Vein endothelial cell (HUVEC) monolayers wa s assessed in vitro. Adhesion molecule receptor expression was assessed flo w cytometrically. Adenosine and some of its receptor-specific analogues dos e-dependently inhibited activated PMN VEGF release. The rank order of poten cy was consistent with the affinity profile of human A(2B) receptors. The i nhibitory effect of adenosine was reversed by 3,7-dimethyl-1-propargylxanth ine, an A(2) receptor antagonist. Adenosine (100 muM) or the A(2B) receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 100 muM) significantly reduc ed PMN transendothelial migration. However. expression of activated PMN bet a (2) integrins and HUVEC ICAM-1 were not significantly altered by adenosin e or NECA. Adenosine attenuates human PMN VEGF release and transendothelial migration via the A(2B) receptor. This provides a novel target for the modulation of PMN-directed vascular hyperpermeability in conditions such as the capillary leak syndrome.