Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

Almawi, WY; Melemedjian, OK

doi:10.1677/jme.0.0280069

Cited by 216 publications

(136 citation statements)

References 74 publications

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“…29,34 GCs mediate these effects through the intracellular glucocorticoid receptor and, depending on the target gene, the complex ligand Á/glucocorticoid receptor may stimulate (transactivation), or alternatively inhibit (transrepression), gene transcription. 30,35 In this work, we show that, in FSDC, the glucocorticoid dexamethasone inhibits iNOS protein expression and nitrite production induced by GM-CSF. Furthermore, dexamethasone also prevents the decrease of IkB-a protein levels, and subsequent NF-kB translocation to the nucleus, induced by GM-CSF (Fig.…”

mentioning

confidence: 52%

“…The anti-inflammatory properties of GCs such as dexamethasone are due to the down-regulation of the expression of immunomodulatory genes, 26,30 thereby inhibiting the expression of enzymes involved in the inflammatory process, namely iNOS, which produces NO in large amounts. 29,34 GCs mediate these effects through the intracellular glucocorticoid receptor and, depending on the target gene, the complex ligand Á/glucocorticoid receptor may stimulate (transactivation), or alternatively inhibit (transrepression), gene transcription.…”

Section: Discussionmentioning

confidence: 99%

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Dexamethasone prevents granulocyte‐macrophage colony‐stimulating factor‐induced nuclear factor‐κB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Vital

Gonçalo

Cruz

et al. 2003

Mediators of Inflammation

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AIMS : Nitric oxide (NO) has been increasingly implicated in inflammatory skin diseases, namely in allergic contact dermatitis. In this work, we investigated the effect of dexamethasone on NO production induced by the epidermal cytokine granulocyte Á / macrophage colony-stimulating factor (GM-CSF) in a mouse fetal skin dendritic cell line.Methods: NO production was assessed by the method of Griess. Expression of the inducible isoform of nitric oxide synthase (iNOS) protein was evaluated by western blot analysis and immunofluorescence microscopy. Western blot analysis was also performed to evaluate cytosolic IkappaB-alpha (IkB-a) protein levels. The electrophoretic mobility shift assay was used to evaluate the activation or inhibition of nuclear factor kappa B (NF-kB).Results : GM-CSF induced iNOS expression and NO production, and activated the transcription factor NF-kB. Dexamethasone inhibited, in a dose-dependent manner, NO production induced by GM-CSF. Addition of dexamethasone to the culture, 30 min before GM-CSF stimulation, significantly inhibited the cellular expression of iNOS. Dexamethasone also inhibited GM-CSF-induced NFkB activation by preventing a significant decrease on the IkB-a protein levels, thus blocking NF-kB migration to the nucleus.Conclusions : The corticosteroid dexamethasone inhibits GM-CSF-induced NF-kB activation, iNOS protein expression and NO production. These results suggest that dexamethasone is a potent inhibitor of intracellular events that are involved on NO synthesis, in skin dendritic cells.Key words: Granulocyte Á/macrophage colony-stimulating factor, Nitric oxide, Transcription factors, Dexamethasone, Skin dendritic cell Mediators of Inflammation, 12(2), 71 Á/78 (April 2003) Dexamethasone prevents granulocyte Á /macrophage colonystimulating factor-induced nuclear factor-kB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line After stimulation by microorganisms and epidermal cytokines, like interferon-g, tumor necrosis factor-a, interleukin 1-b and granulocyte Á/macrophage colony-stimulating factor (GM-CSF), Langerhans and other dendritic skin antigen presenting cells produce NO, 16 Á 18 which may be important in the process of antigen presentation to T cells. 19,20 We have previously shown, using a mouse fetal skin dendritic cell line (FSDC) in culture, that GM-CSF, a cytokine produced by allergen-stimulated keratinocytes that promotes Langerhans cell maturation and antigen presentation, induces NO production. 21 This is dependent on the expression of iNOS and is associated with the activation of the transcription nuclear factor kappa B (NF-kB). 22 This transcription factor is present in a latent (inactive) state in the cytoplasm, bound to an inhibitor, IkappaB (IkB). 23 Exposure of cells to a variety of physiological and non-physiological stimuli induces phosphorylation, and subse- 24 This process releases NF-kB from this inhibitor, enabling it to translocate to the nucleus, 25 where it increases the expression...

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mentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Dexamethasone prevents granulocyte‐macrophage colony‐stimulating factor‐induced nuclear factor‐κB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Vital

Gonçalo

Cruz

et al. 2003

Mediators of Inflammation

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“…As well as the coactivators or histone deacetylase, other nuclear proteins can interact with NF-κB and modulate its activity positively or negatively. The transcription factor Twist [7] and glucocorticoid receptor [8] interact directly with p65 and repress p65-mediated transcriptional activation. Reportedly, c-myc [9], p202a [10] and prostaglandins [11] also negatively regulate NF-κB in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Matsuo

Yamazaki

Takeshige

et al. 2007

Biochemical Journal

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IκB-ζ [inhibitor of NF-κB (nuclear factor κB) ζ ] is a nuclear protein that is induced upon stimulation of TLRs (Toll-like receptors) and IL (interleukin)-1 receptor. IκB-ζ harbours Cterminal ankyrin repeats that interact with NF-κB. Our recent studies have shown that, upon stimulation, IκB-ζ is essential for the induction of a subset of inflammatory genes, represented by IL-6, whereas it inhibits the expression of TNF (tumour necrosis factor)-α. In the present study, we investigated mechanisms that determine the different functions of IκB-ζ . We found that coexpression of IκB-ζ and the NF-κB subunits synergistically activates transcription of the hBD-2 (human β-defensin 2) and NGAL (neutrophil gelatinase-associated lipocalin) genes, whereas it inhibits transcription of E-selectin. Reporter analyses indicated that, in addition to an NF-κB-binding site, a flanking C/EBP (CCAAT/enhancer-binding protein)-binding site in the promoters is essential for the IκB-ζ -mediated transcriptional activation. Using an artificial promoter consisting of the NF-κB-and C/EBP-binding sites, transcriptional activation was observed upon co-transfection with IκB-ζ and NF-κB, indicating that these sequences are minimal elements that confer the IκB-ζ -mediated transcriptional activation. Chromatin immunoprecipitation assays and knockdown experiments showed that both IκB-ζ and the NF-κB subunits were recruited to the NGAL promoter and were essential for the transcriptional activation of the hBD-2 and NGAL promoters on stimulation with IL-1β. The activation of the NGAL promoter by transfection of IκB-ζ and NF-κB was suppressed in C/EBPβ-depleted cells. Thus IκB-ζ acts as an essential transcriptional activator by forming a complex with NF-κB on promoters harbouring the NF-κB-and C/EBP-binding sites, upon stimulation of TLRs or IL-1 receptor.Key words: CCAAT/enhancer-binding protein (C/EBP), inflammation, inhibitor of nuclear factor κB ζ (IκB-ζ ), innate immunity, nuclear factor κB (NF-κB), transcription.

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“…Thus, glucocorticoids stimulate proteasome expression (at least the C3 subunit) by antagonising the interaction of NF-kB with its response element in the proteasome promoter region. Glucocorticoids also induce gene transcription and protein synthesis of the NF-kB inhibitor, IkB, and inhibit the expression of cytokines (Almawi and Melemedjian, 2002). In contrast, induction of protein degradation by TNF-a, which is also mediated through the ubiquitin -proteasome proteolytic pathway (Li et al, 1998), appears to be mediated through proteasomal degradation of IkBa and translocation of NF-kB to the nucleus (Li and Reid, 2000).…”

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confidence: 99%

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

2005

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Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-kB (NFkB) in regulating muscle protein degradation and expression of the ubiquitin -proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C 2 C 12 myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-kBa, an NF-kB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-kBa, nuclear accumulation of NF-kB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-kBa proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-kB. Proteolysis-inducing factor also induced increased expression of the ubiquitinproteasome pathway, as determined by 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the b-subunits of the proteasome, protein expression of 20S a-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E2 14k , in cells containing wild-type, but not mutant, I-kBa. The ability of mutant I-kBa to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin -proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kB.

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Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

Cited by 216 publications

References 74 publications

Dexamethasone prevents granulocyte‐macrophage colony‐stimulating factor‐induced nuclear factor‐κB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Dexamethasone prevents granulocyte‐macrophage colony‐stimulating factor‐induced nuclear factor‐κB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

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