cAMP targeting of p38 MAP kinase inhibits thrombin-induced NF-kappaB activation and ICAM-1 expression in endothelial cells.
We investigated the mechanisms by which elevated intracellular cAMP concentration inhibits the thrombin-induced ICAM-1 expression in endothelial cells. Exposure of human umbilical vein endothelial cells to forskolin or dibutyryl cAMP, which increase intracellular cAMP by separate mechanisms, inhibited the thrombin-induced ICAM-1 expression. This effect of cAMP was secondary to inhibition of NF-kappaB activity, the key regulator of thrombin-induced ICAM-1 expression in endothelial cells. The action of cAMP occurred downstream of IkappaBalpha degradation and was independent of NF-kappaB binding to the ICAM-1 promoter. We observed that cAMP interfered with thrombin-induced phosphorylation of NF-kappaB p65 (RelA) subunit, a crucial event promoting the activation of the DNA-bound NF-kappaB. Because p38 MAPK can induce transcriptional activity of RelA/p65 without altering the DNA binding function of NF-kappaB, we addressed the possibility that cAMP antagonizes thrombin-induced NF-kappaB activity and ICAM-1 expression by preventing the activation of p38 MAPK. We observed that treating cells with forskolin blocked the activation of p38 MAPK, and inhibition of p38 MAPK interfered with phosphorylation of RelA/p65 induced by thrombin. Our data demonstrate that increased intracellular cAMP concentration in endothelial cells prevents thrombin-induced ICAM-1 expression by inhibiting p38 MAPK activation, which in turn prevents phosphorylation of RelA/p65 and transcriptional activity of the bound NF-kappaB.
Rahman
Arshad
A
Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York 14642, USA. Arshad_Rahman@urmc.rochester.edu
Anwar
Khandaker N
KN
Minhajuddin
Mohd
M
Bijli
Kaiser M
KM
Javaid
Kamran
K
True
Andrea L
AL
Malik
Asrar B
AB
D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D051996:Transcription Factor RelA; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D006490:Hemostatics; D016328:NF-kappa B; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin