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B-
in Endothelial Cell Activation1

*
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Womens Hospital and Harvard Medical School, Boston, MA 02115; and
Medical Clinic II, Johannes Gutenberg University, Mainz, Germany
The NF-
B inhibitor I
B-
is a new member of the I
B
protein family, but its functional role in regulating NF-
B-mediated
induction of adhesion molecule expression is unknown. In vascular
endothelial cells, I
B-
associates predominantly with the NF-
B
subunit Rel A and to a lesser extent with c-Rel, whereas I
B-
and
I
B-ß associate with Rel A only. Following stimulation with
TNF-
, pyrrolidine dithiocarbamate (PDTC),
N-acetylcysteine, and dexamethasone prevented I
B
kinase-induced I
B-
, but not I
B-ß or I
B-
phosphorylation and degradation. Since the activation of NF-
B is
required for the induction of adhesion molecule expression, we examined
the role of I
B-
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 I
B-
inhibited ICAM-1 and VCAM-1
promoter activity in endothelial cells. These findings indicate that
c-Rel-associated I
B-
is involved in the induction of ICAM-1
expression.
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