Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma - The role of constitutive NF-kappa B activity

Atherogenesis involves cellular immune responses and altered vascular smooth muscle cell (SMC) function. Cytokines such as interleukin (IL)-1 alpha and interferon-gamma (TFN-gamma) may contribute to this process by activating SMC. To determine whether the anti-atherogenic mediator, nitric oxide ((NO)-N-.), can modulate cytokine-induced SMC activation, we investigated the effects of various (NO)-N-.-generating compounds on the expression of intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). Induction of ICAM-1 expression by IL-1 alpha and VCAM-1 expression by IFN-gamma was attenuated by (NO)-N-. 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)-N-. repressed IFN-gamma-induced VCAM-1 gene transcription, in part, through inhibition of nuclear factor-kappa B (NF-kappa B). Electrophoretic mobility shift assay revealed that SMC possess basal constitutive NF-kappa B activity, which was augmented by treatment with IL-1 alpha. In contrast, IFN-gamma induced and activated interferon regulatory factor (IRF)-1 but had little effect on basal constitutive NF-kappa B activity. (NO)-N-. donors had no inhibitory effect on IRF-1 activation but did inhibit basal and IL-1 alpha-stimulated NF-kappa B activation. These findings suggest that the induction of ICAM-1 and VCAM-1 expression requires NF-kappa B activation and that (NO)-N-. attenuates IFN-gamma-induced VCAM-1 expression primarily by inhibiting basal constitutive NF-kappa B activity in SMC.