Review Article
Nitric oxide: an inhibitor of NF-κB/Rel system in glial cells

https://doi.org/10.1016/S0361-9230(00)00262-8Get rights and content

Abstract

Nitric oxide (NO) has been reported to regulate NF-κB, one of the best-characterized transcription factors playing important roles in many cellular responses to a large variety of stimuli. NO has been suggested to induce or inhibit the activation of NF-κB, its effect depending, among others, on the cell type considered. In this review, the inhibitory effect of NO on NF-κB (and subsequent suppression of NF-κB-dependent gene expression) in glial cells is reported. In particular, exogenous and endogenous NO has been observed to keep NF-κB suppressed, thus preventing the expression of NF-κB-induced genes, such as inducible NO synthase itself or HIV-1 long terminal repeat. Furthermore, the possible molecular mechanisms of NO-mediated NF-κB inhibition are discussed. More specifically, NO has been reported to suppress NF-κB activation inducing and stabilizing the NF-κB inhibitor, IκB-α. On the other hand, NO may inhibit NF-κB DNA binding through S-nitrosylation of cysteine residue (i.e., Cys62) of the p50 subunit. As a whole, a novel concept that the balance of intracellular NO levels may control the induction of NF-κB in glial cells has been hypothesized.

Section snippets

The NF-κB/Rel system

More than a decade ago, NF-κB was first described as a protein that bounds specifically to a DNA sequence (5′-GGGACTTTCC-3′) in the intronic enhancer of the immunoglobulin κ light chain gene [59]. Over the years, it became evident that NF-κB is a member of the larger NF-κB/Rel family of transcriptional factors, which includes p50 (NF-κB1), p52 (NF-κB2), p65 (RelA), RelB, and c-rel. NF-κB/Rel proteins exist as homo- or heterodimers and are sequestered in an inactive form through noncovalent

NO production and NF-κB-mediated NOS-II expression in glial cells

NF-κB represents the major transcriptional factor also in the NOS-II transcriptional induction occurring in glial cells. In particular, NF-κB mediates Escherichia coli lypopolysaccharide (LPS)-induced NOS-II gene expression in primary astrocytes [6], C6 glioma cells [44], and in cultured microglia [20]. Furthermore, NF-κB has been found to mediate NOS-II induction by other inducers, including interferon-γ (IFNγ) 4, 40, interleukin-1β (IL-1β) [5], tumor necrosis factor-α (TNFα) [40],

NO inhibition of NF-κB-induced NOS-II expression in glial cells

Using human ramified microglial cells (which express no constitutive NOS isoforms), it has been then confirmed that a pre-treatment of cells with nearly physiological levels of exogenous NO suppressed NOS-II mRNA expression as elicited by LPS plus TNFα, this effect being ascribed to an inhibitory action of pre-existing low levels of NO on NF-κB activation [9]. Thereafter, this notion has met a wide consensus in a number of biological systems, thus pointing out the direct implication of NF-κB in

NF-κB: a point of convergence of the cross-talk between constitutive and inducible NOS isoforms in glial cells

Altogether these results suggest that constitutive NO, as produced physiologically in glial cells, serves to keep NF-κB suppressed, thus preventing NOS-II induction. Though intriguing, this concept leaves a puzzling paradox pending: the NF-κB activation and the subsequent induction of NOS-II expression should be a rather rare event in cells containing both constitutive and inducible NOS isoforms, or more generally in any tissue capable of expressing NOS-II when exposed to a physiological level

NO inhibition of NF-κB-induced HIV-1 LTR in glial cells

NF-κB has been reported to be involved in the replication of viruses, including HIV-1. In astroglial cells, HIV-1 infection is poorly productive, being typified by a persistent state of infection in which few or no viral structural antigens are expressed [66]. However, HIV-1 replication may be induced by the activation and binding of NF-κB to the consensus sequences on viral long terminal repeat (LTR) promoter [24]. Recently, using transfected human astroglial cells, it has been demonstrated

Mechanisms of NF-κB inhibition by NO

So far, two mechanisms have been identified by which NO may inhibit NF-κB action (Fig. 1). First, NO is able to suppress NF-κB activation inducing and stabilizing the NF-κB inhibitor, IκB-α [49]. In particular, two NO donors, SNP and S-nitrosoglutathione, inhibit NF-κB activation in human vascular endothelial cells stimulated with TNFα. In this respect, NO stabilizes IκB-α by preventing its degradation from NF-κB and increases the mRNA expression of IκB-α without affecting the mRNA expression

NO effect on NF-κB activation in other cell types

Inhibitory NO effects on NF-κB-dependent gene expression and functions have been also demonstrated in a variety of cells, including endothelial cells 13, 31, 33, 50, 51, 62, 63, 69, 73, 74 (although low concentrations of NO has been shown to enhance the pre-activation of NF-κB by TNFα or phorbol myristate acetate (PMA) [69]), smooth muscle cells 60, 68, macrophages 7, 16, 57, mesangial cells (a dual effect of NO donors on NF-κB activation has been reported to be dependent on the time of

Concluding remarks

The modulation of NF-κB system by NO has been well established. Whether NO inhibits or activates NF-κB depends, among others, on the concentration, source, time of treatment, redox state, stimulus, and the cell type. In glial cells, where the inhibitory effect on NF-κB appears to be the prevalent NO function, a novel concept comes forwards that the balance between down- and up-regulation of the intracellular NO levels may control the induction of NF-κB. Hence, it is challenging to assume that a

Acknowledgements

We thank Prof. H. Suzuki, Prof. G. Venturini and Prof. P. Ascenzi for helpful discussion. We also thank Mr. M. Muolo for preparation of figures and Mrs. L. Mattace for editorial assistance. This work was supported by the current research project of Italian Minister of Health.

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