Bilirubin effect on endothelial adhesion molecules expression is mediated by the NF-kappaB signaling pathway.
We have recently demonstrated that unconjugated bilirubin (UCB) limits the overexpression of adhesion molecules and inhibits the PMN endothelial adhesion induced by the pro-inflammatory cytokine TNFalpha. To understand the molecular events involved we investigated whether the inhibitory effect is determined by a direct influence of UCB on different nuclear pathways. Co-treatment of cells with UCB, TNFalpha, and pyrridoline dithiocarbamate (PDTC), a NF-kappaB inhibitor, additively enhanced the inhibitory effect of UCB. UCB prevented the nuclear translocation of NF-kappaB induced by TNFalpha. The failure of UCB to alter TNFalpha-induced phosphorylation of cAMP-response element-binding protein (CREB) suggested that the CREB pathway is not involved in the UCB inhibition and that UCB blunting effect on the overexpression of adhesion molecules occurs via inhibition of the NF-kappaB transduction pathway. Collectively these data may contribute to explain the protective effect of bilirubin against development of atherosclerosis.
Mazzone
Graciela Luján
GL
Centro Studi Fegato, Trieste, Italy.
Rigato
Igino
I
Ostrow
J Donald
JD
Tiribelli
Claudio
C
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D011392:Proline; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D001663:Bilirubin