Nitric Oxide Attenuates Vascular Smooth Muscle Cell Activation by Interferon-γ

Abstract

Atherogenesis involves cellular immune responses and altered vascular smooth muscle cell (SMC) function. Cytokines such as interleukin (IL)-1 alpha and interferon-gamma (IFN-gamma) 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-1 alpha and VCAM-1 expression by IFN-gamma 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 acetyl-transferase reporter gene showed that .NO 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 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 attenuates IFN-gamma-induced VCAM-1 expression primarily by inhibiting basal constitutive NF-kappa B activity in SMC.

Constitutive Activation of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Gene Transcription by IRF1 and IRF2 during Restricted EBV Latency

“…In contrast, this report and previously published data (89) suggest that the G-14 variants have a reduced affinity for ISGF3␥ but bind IRF1 and IRF2 with high affinity. The latter ICS elements are not IFN responsive and are capable of constitutively activating transcription (14,26,48,74).…”

“…Similar to the histone H4 genes, the only known requirement for EBNA1 in EBV-infected cells involves the binding of EBNA1 to the EBV latent origin of replication (oriP) during S phase of the cell cycle, thereby allowing the EBV episome to be replicated coordinately with cellular genomic DNA (98,99). Thus, EBNA1 might be produced in a cell cycle-regulated manner, with peak production occurring [40], histone H4 [88], PRDI [89], IFN-␣1 [14], VCAM1 [74], TAP1 [48], H2K b IRS [30], factor B [96], 2Ј-5Ј OAS [66], and 6-16 [59]). The nucleotide at position 14, which appears to correlate with IFN-␣/␤ inducibility, is boxed.…”

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

“…This finding is of particular interest considering the complex role exerted by nitric oxide in the homeostasis of endothelial cells [18,19] and in the regulation of leukocyte-endothelium interaction [20][21][22]. In this regard, it is well known that an acute decrease in NO production by the vascular endothelium up-regulates endothelial cell adhesion molecule expression (i.e., P-selectin and ICAM-1), thus enhancing leukocyte-endothelial interaction [12,[23][24][25].…”

Effect of Redox Modulation on Xenogeneic Target Cells: The Combination of Nitric Oxide and Thiol Deprivation Protects Porcine Endothelial Cells from Lysis by IL-2-Activated Human NK Cells

“…Others have found that treatment with NO donors, such as SNAP, suppressed the NF-B DNA-binding activation in human EC (75) and vascular smooth muscle cells (76). In the current study, SNAP pretreatment alone was not sufficient to inhibit NF-B DNA-binding activity in TNF-␣-activated porcine ECs.…”