ELEVATED CYCLIC-AMP INHIBITS ENDOTHELIAL-CELL SYNTHESIS AND EXPRESSION OF TNF-INDUCED ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULE-1, AND VASCULAR CELL-ADHESION MOLECULE-1, BUT NOT INTERCELLULAR-ADHESION MOLECULE-1

We have investigated the role of cAMP as a signal transducer for TNF-i nduction of leukocyte adhesion molecule expression in cultured human u mbilical vein endothelial cells (EC). Forskolin, a stimulator of adeny late cyclase, either alone or in combination with isobutyl methylxanth ine (IBMX), an inhibitor of phosphodiesterase, fails to induce express ion of endothelial leukocyte adhesion molecule 1 (ELAM-1 or E-selectin ), of vascular cell adhesion molecule 1 (VCAM-1) or of intercellular a dhesion molecule 1 (ICAM-1 or CD54). Unexpectedly, this combination of cAMP-elevating drugs inhibits TNF induction of ELAM-1 and VCAM-1 but not ICAM-1 expression. Similar results were observed with the membrane -permeant cAMP mimetics 8 bromoadenosine 3':5' cyclic monophosphate (8 Br-cAMP) and N(6)2'-O-dibutyryladenosine 3':5'-cyclic monophosphate. I nhibition was greater at lower TNF concentrations (<10 U/ml), at highe r 8 Br-cAMP concentrations (>100 muM), and at early times (2 h). Forsk olin plus IBMX selectively inhibits TNF-induced increases in ELAM-1 an d VCAM-1 mRNA, indicating that the action of cAMP is to block synthesi s of these molecules. TNF, through stimulation of prostaglandin synthe sis, produces slight elevations in the levels of endothelial cAMP. How ever, these increases in cAMP appear too small compared to those induc ed by forskolin plus IBMX to inhibit adhesion molecule expression. Ind eed, complete inhibition of the TNF-mediated rise in cAMP, achieved by blocking cyclooxygenase with indomethacin, does not alter ELAM-1 expr ession. We conclude that cAMP is neither an intracellular mediator nor a physiological regulator of TNF-induced adhesion molecule expression in EC. However, our findings suggest that pharmacological elevations of cAMP in EC, by inhibiting TNF-induced synthesis of ELAM-1 and VCAM- 1, could serve to limit inflammation.