Simvastatin modulates cytokine-mediated endothelial cell adhesion moleculeinduction: Involvement of an inhibitory G protein

Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and VCAM-1 p lay variably important roles in immune-mediated processes. They are induced by the proinflammatory cytokines IL-1 and TNF-alpha, and NF-kappaB is requ ired for the regulated expression of all three genes, Regulators of this pa thway 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, pretreatme nt 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, Northe rn blot analysis demonstrated an increase in steady state IL-1-induced E-se lectin mRNA levels in cells pretreated with simvastatin, This was associate d with an increase in nuclear translocation of NF-KB, as detected by EMSA, The effect of simvastatin was reversed by mevalonate and geranylgeranyl pyr ophosphate but not squalene, indicating that an inhibitory prenylated prote in is involved in endothelial responses to proinflammatory cytokines, Pertu ssis toxin mimicked the effect of simvastatin, and the G protein activator NaF inhibited the cytokine-induced expression of endothelial CAMs, indicati ng that a G(i alpha) protein is involved. These results demonstrate that cy tokine-mediated activation of the endothelium, and specifically CAM inducti on, can be modulated by a heterotrimeric G protein-coupled pathway, This ma y represent a "basal tone" of endothelial inactivation, which can either be disinhibited or amplified, depending on the stimulus.