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Division of Cardiovascular Medicine and Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536; and
Unit of Clinical Immunology, Department of Biological and Technical Research, San Raffaele Scientific Institute, Milan, Italy
Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and
VCAM-1 play variably important roles in immune-mediated processes. They
are induced by the proinflammatory cytokines IL-1 and TNF-
, and
NF-
B is required for the regulated expression of all three genes.
Regulators of this pathway could potentially be potent immune
modulators. We studied the effect of a 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor, simvastatin, on cytokine-induced
expression of CAMs in HUVEC. Unexpectedly, pretreatment with
simvastatin potentiated the induction of all three endothelial CAMs by
IL-1 and TNF, but not LPS or PMA, as detected by flow cytometry.
Northern blot analysis demonstrated an increase in steady state
IL-1-induced E-selectin mRNA levels in cells pretreated with
simvastatin. This was associated with an increase in nuclear
translocation of NF-B, as detected by EMSA. The effect of
simvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate
but not squalene, indicating that an inhibitory prenylated protein is
involved in endothelial responses to proinflammatory cytokines.
Pertussis toxin mimicked the effect of simvastatin, and the G protein
activator NaF inhibited the cytokine-induced expression of endothelial
CAMs, indicating that a Gi protein is involved. These
results demonstrate that cytokine-mediated activation of the
endothelium, and specifically CAM induction, can be modulated by a
heterotrimeric G protein-coupled pathway. This may represent a "basal
tone" of endothelial inactivation, which can either be disinhibited
or amplified, depending on the stimulus.
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