Suppression of endothelial adhesion molecule up-regulation with cyclopentenone prostaglandins is dissociated from IkappaB-alpha kinase inhibition and cell death induction.
The cyclopentenone prostaglandins (cPG) 15-deoxy-Delta12,14-prostaglandin J2 (dPGJ2) and PGA1 can inhibit multiple steps in nuclear factor (NF)-kappaB signaling and can induce cell death. Here we characterized the effects of dPGJ2 and PGA1 on the inflammatory induction of endothelial cell adhesion molecules (CAM). Pretreatment of endothelial cells with dPGJ2 or PGA1 at low concentrations dose dependently inhibited the up-regulation of CAM expression and monocyte arrest by tumor necrosis factor (TNF)-alpha but not expression of inhibitor of apoptosis proteins. Only at high concentrations, cPG enhanced TNF-alpha-induced cell death and inhibited TNF-alpha-induced IkappaB-alpha kinase (IKK) activation, IkappaB-alpha degradation, and NF-kappaB/p65 translocation, while promoting AP-1/c-jun phosphorylation. Expression of an IKK-beta mutant (C179A) resistant to interaction with cPG impaired cell death induction but not inhibition of CAM up-regulation by cPG. Gel shift and reporter gene analysis revealed that cPG at low concentrations directly impaired DNA binding of NF-kappaB and NF-kappaB-dependent transactivation. The synthetic analogs dPGA1 or dPGA2 were ineffective, indicating structural specificity of cPG. Thus, the suppression of endothelial CAM up-regulation with cPG is dissociated from cell death sensitization and IKK inhibition above threshold concentrations and related to interference with NF-kappaB binding. Our findings define distinct mechanisms for anti-inflammatory and proapoptotic effects of cPG in endothelial cells.
Zernecke
Alma
A
Institut für Prophylaxe der Kreislaufkrankheiten, Ludwig-Maximilians-Universität München, 80336 München, Germany.
Erl
Wolfgang
W
Fraemohs
Line
L
Lietz
Michael
M
Weber
Christian
C
D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011454:Prostaglandins A / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D015815:Cell Adhesion Molecules; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011454:Prostaglandins A; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D015230:Prostaglandin D2; C100573:prostaglandin A1