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-induction of leukocyte adhesion molecule expression in cultured human umbilical vein endothelial cells (EC). Forskolin, a stimulator of adenylate cyclase, either alone or in combination with isobutyl methylxanthine (IBMX), an inhibitor of phosphodiesterase, fails to induce expression of endothelial leukocyte adhesion molecule 1 (ELAM-1 or E-selectin), of vascular cell adhesion molecule 1 (VCAM-1) or of intercellular adhesion 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 (8Br-cAMP) and N(6)2'-O-dibutyryladenosine 3':5'-cyclic monophosphate. Inhibition was greater at lower TNF concentrations (< 10 U/ml), at higher 8 Br-cAMP concentrations (> 100 microM), and at early times (2 h). Forskolin plus IBMX selectively inhibits TNF-induced increases in ELAM-1 and VCAM-1 mRNA, indicating that the action of cAMP is to block synthesis of these molecules. TNF, through stimulation of prostaglandin synthesis, produces slight elevations in the levels of endothelial cAMP. However, these increases in cAMP appear too small compared to those induced by forskolin plus IBMX to inhibit adhesion molecule expression. Indeed, complete inhibition of the TNF-mediated rise in cAMP, achieved by blocking cyclooxygenase with indomethacin, does not alter ELAM-1 expression. 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.