IL-4, BUT NOT TUMOR-NECROSIS-FACTOR-ALPHA, INCREASES ENDOTHELIAL-CELLADHESIVENESS FOR LYMPHOCYTES BY ACTIVATING A CAMP-DEPENDENT PATHWAY

IL-4 and TNF-alpha increase endothelial cell adhesiveness for PBL by p romoting the expression of adhesion molecules. We investigated the int racellular cAMP involvement in the increased endothelial cell adhesivi ty induced by IL-4 or TNF-alpha. We showed that both IL-4 and TNF-alph a increased intracellular cAMP in endothelial cells (EC). Furthermore, dibutyryl-cAMP and forskolin (which increased intracellular cAMP) inc reased basic EC adhesivity for PBL. The co-stimulation of EC with cAMP elevating agents and TNF-alpha, but not IL-4, resulted in an additive increase in EC adhesiveness. 2',5' dideoxyadenosine, an inhibitor of adenylate cyclase, decreased PBL adhesion to IL-4- but not TNF-alpha-t reated EC. Similarly, HA1004, a protein kinase A inhibitor, totally re versed the IL-4 but not TNF-alpha effect on EC adhesiveness, whereas H 7, a protein kinase C inhibitor, did not antagonise cytokine-enhanced EC adhesivity. These results indicate that IL-4, but not TNF-alpha, us es a cAMP-dependent pathway to increase PBL adhesion. Furthermore, we showed that cAMP elevation in EC did not induce vascular cell adhesion molecule 1, the only identified adhesion molecule induced by IL-4, in dicating that a rise in cAMP in EC promotes an as yet unidentified adh esion pathway. Our results show that IL-4 increases EC adhesiveness fo r PBL through activation of protein kinase A by promoting an unidentif ied adhesion pathway.