Action of cAMP on expression and release of adhesion molecules in human endothelial cells.
The expression of E-selectin induced by tumor necrosis factor (TNF) on the surface of human umbilical vein endothelial cells (HUVEC) was partially inhibited by an increase in the level of adenosine 3',5'-cyclic monophosphate (cAMP), produced by forskolin or cholera toxin combined with the type IV phosphodiesterase inhibitor rolipram and the protein kinase A agonist phosphorothioate analogue of cAMP SpcAMPS. The same agents had no significant effect on the constitutive and TNF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1), whereas the effect on vascular cell adhesion molecule 1 (VCAM-1) expression was variable depending on cell culture conditions. The stimulatory effects of phorbol 12-myristate 13-acetate and bacterial lipopolysaccharide (LPS) on E-selectin expression were also downregulated by the forskolin-rolipram combination and by SpcAMPS. Inhibition of the surface expression of E-selectin was associated with a decrease of the total amount of the protein in the cell lysate and a reduced mRNA level, with no significant effect on mRNA stability. In anesthetized rats, the terbutaline-rolipram combination reduced the rolling of leukocytes induced by LPS in the mesenteric microcirculation. In addition to their partial inhibitory effect on the TNF-induced surface expression of E-selectin on HUVEC, the forskolin-rolipram combination and SpcAMPS strongly inhibited the release of soluble E-selectin from these cells; the release of soluble ICAM-1 and VCAM-1 was unaffected by these agents. Isoproterenol reduced the release of soluble E-selectin, whereas it had no significant effect on the cell surface expression of the protein. This study underscores the potential anti-inflammatory effect of a rise in the endothelial cAMP level.
Morandini
R
R
Laboratory of Oncology and Experimental Surgery, Jules Bordet Institute, Université Libre de Bruxelles, Belgium.
Ghanem
G
G
Portier-Lemarié
A
A
Robaye
B
B
Renaud
A
A
Boeynaems
J M
JM
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D020889:Rolipram; D013566:Sympathomimetics / Q000494:pharmacology; D013726:Terbutaline / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D013566:Sympathomimetics; D005576:Colforsin; D000242:Cyclic AMP; D020889:Rolipram; D013726:Terbutaline