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A Functional Role of IB- in Endothelial Cell Activation¹

Martin Spiecker^*, Harald Darius^* and James K. Liao^2,

^* Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and Medical Clinic II, Johannes Gutenberg University, Mainz, Germany

The NF-B inhibitor IB- is a new member of the IB protein family, but its functional role in regulating NF-B-mediated induction of adhesion molecule expression is unknown. In vascular endothelial cells, IB- associates predominantly with the NF-B subunit Rel A and to a lesser extent with c-Rel, whereas IB- and IB-ß associate with Rel A only. Following stimulation with TNF-, pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine, and dexamethasone prevented IB kinase-induced IB-, but not IB-ß or IB- phosphorylation and degradation. Since the activation of NF-B is required for the induction of adhesion molecule expression, we examined the role of IB- in the transactivation of promoters from VCAM-1, ICAM-1, and E-selectin. Using reporter gene constructs of adhesion molecule promoters, PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 promoter activity. Subcloning of B cis-acting elements of VCAM-1, E-selectin, and ICAM-1 into a heterologous promoter construct revealed that PDTC inhibited VCAM-1 and E-selectin, but to a lesser extent, ICAM-1 B promoter activity. By electrophoretic mobility shift assay, NF-B heterodimers containing c-Rel specifically bind to the B motif in the ICAM-1, but not VCAM-1 or E-selectin promoter. Indeed, overexpression of c-Rel induced ICAM-1 B promoter activity to a greater extent than that of E-selectin and overexpression of IB- inhibited ICAM-1 and VCAM-1 promoter activity in endothelial cells. These findings indicate that c-Rel-associated IB- is involved in the induction of ICAM-1 expression.