NITRIC OXIDE ATTENUATES VASCULAR SMOOTH MUSCLE CELL ACTIVATION BY INTERFERON-GAMMA : THE ROLE OF CONSTITUTIVE NF-KAPPA B ACTIVITY

Abstract Atherogenesis involves cellular immune responses and altered vascular smooth muscle cell (SMC) function. Cytokines such as interleukin (IL)-1α and interferon- (IFN-) may contribute to this process by activating SMC. To determine whether the anti-atherogenic mediator, nitric oxide (NO), can modulate cytokine-induced SMC activation, we investigated the effects of various NO-generating compounds on the expression of intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). Induction of ICAM-1 expression by IL-1α and VCAM-1 expression by IFN- was attenuated by NO donors but not by cGMP analogues. Nuclear run-on assays and transfection studies using various VCAM-1 promoter constructs linked to the chloramphenicol acetyltransferase reporter gene showed that NO repressed IFN--induced VCAM-1 gene transcription, in part, through inhibition of nuclear factor-κ B (NF-κB). Electrophoretic mobility shift assay revealed that SMC possess basal constitutive NF-κB activity, which was augmented by treatment with IL-1α. In contrast, IFN- induced and activated interferon regulatory factor (IRF)-1 but had little effect on basal constitutive NF-κB activity. NO donors had no inhibitory effect on IRF-1 activation but did inhibit basal and IL-1α-stimulated NF-κB activation. These findings suggest that the induction of ICAM-1 and VCAM-1 expression requires NF-κB activation and that NO attenuates IFN--induced VCAM-1 expression primarily by inhibiting basal constitutive NF-κB activity in SMC.