Inhibition of NFkB DNA binding activity by glucocorticoids in rat brain

Unlap, Tino; Jope, Richard S.

doi:10.1016/0304-3940(95)11963-w

Cited by 63 publications

(30 citation statements)

References 14 publications

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“…Commensurate with that, in unstressed rats, GR antagonists increase LPS-induced NFκB DNA binding activity in the frontal cortex and hippocampus (Munhoz et al 2006). Moreover, dexamethasone treatment decreases basal NFκB DNA binding activity in cortex and hippocampus (Unlap and Jope 1995;Unlap and Jope 1997) and also following LPS treatment (Wang et al 2006) (however there are some caveats to this interpretation that will be discussed later. )…”

Section: 3mentioning

confidence: 68%

An inflammatory review of glucocorticoid actions in the CNS

Sorrells¹,

Sapolsky²

2007

Brain, Behavior, and Immunity

388

283

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In recent years the classic view that glucocorticoids, the adrenal steroids secreted during stress, are universally anti-inflammatory has been challenged at a variety of levels. It was first observed that under some circumstances, acute GC exposure could have pro-inflammatory effects on the peripheral immune response. More recently, chronic exposure to GCs has been found to have pro-inflammatory effects on the specialized immune response to injury in the central nervous system. Here we review the evidence that in some cases, glucocorticoids can increase pro-inflammatory cell migration, cytokine production, and even transcription factor activity in the brain. We consider how these unexpected effects of glucocorticoids can co-exist with their well-established anti-inflammatory properties, as well as the considerable clinical implications of these findings.

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Section: 3mentioning

confidence: 68%

An inflammatory review of glucocorticoid actions in the CNS

Sorrells¹,

Sapolsky²

2007

Brain, Behavior, and Immunity

388

283

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“…Prednisolone is a glucocorticoid (GC), known to affect NF-B activation (35), a transcription factor controlling many genes important for immunity, inflammation, cell proliferation, and apoptosis. Our data show that, in proliferating PASMC, treatment with PDGF caused nuclear translocation of NF-B verified by significantly increased p65 and p50 protein levels in nuclei (Figs.…”

Section: Discussionmentioning

confidence: 99%

Prednisolone inhibits PDGF-induced nuclear translocation of NF-κB in human pulmonary artery smooth muscle cells

Ogawa¹,

Firth²,

Yao³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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inhibits PDGF-induced nuclear translocation of NF-B in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 295: L648 -L657, 2008. First published August 15, 2008 doi:10.1152/ajplung.90245.2008.-Pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH), is partially due to increased proliferation of pulmonary arterial smooth muscle cells (PASMC) in the media, resulting in vascular wall thickening. Plateletderived growth factor (PDGF) is a potent mitogen that may be involved in the progression of PAH. Blockade of PDGF receptors has been demonstrated to have therapeutic potential for patients with severe pulmonary hypertension. Prednisolone is an immunosuppressant shown to have anti-inflammatory and antiproliferative effects on PASMC. This study was designed to investigate whether PDGF and prednisolone affect human PASMC proliferation by regulating the nuclear translocation of NF-B (a transcription factor composed of 2 subunits, p50 and p65). Treatment of human PASMC with PDGF (10 ng/ml) significantly increased nuclear translocation of p50 and p65 subunits. Inhibition of NF-B activation or nuclear translocation of p50/p65 significantly attenuated PDGF-induced PASMC proliferation (determined by [ 3 H]thymidine incorporation). In the presence of prednisolone (200 M), the PDGF-induced nuclear translocation of p50 and p65 subunits was markedly inhibited (P Ͻ 0.05 vs. the cells treated with PDGF alone). These results indicate that PDGF-induced nuclear translocation of NF-B may play an important role in stimulating PASMC proliferation (and/or enhancing PASMC survival), whereas prednisolone may exert anti-inflammatory and antiproliferative effects on PASMC by inhibiting NF-B nuclear translocation. proliferation; pulmonary arterial hypertension; immunosuppressant; therapy PULMONARY VASCULAR REMODELING is a major contributor to the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. Increased growth factors (e.g., PDGF) and enhanced inflammatory responses (characterized with cytokines and chemokines that can stimulate or activate NF-B) have recently been demonstrated to be important causes for the development of pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (26,29). Prednisolone is an anti-inflammatory and immunosuppressive drug widely used for treatment of bronchial asthma, chronic obstructive pulmonary disease, autoimmune disease, and leukemia (2,6,17,23,28). Prednisolone is also routinely used postoperatively in patients with IPAH who have undergone lung transplantation (24, 42). The use of immunosuppressants to treat pulmonary hypertension has shown promising beneficial effects in some patients (4,19). In addition to its immunosuppressive effects, prednisolone has been shown to inhibit PDGF-stimulated proliferation of pulmonary artery smooth muscle cells (PASMC) from p...

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“…Electrophoretic Mobility Shift Assay (EMSA)-EMSAs were performed using a double-stranded 15-bp oligonucleotide (5Ј-AGT TGA GGG GAC TTT CCC AGG C-3Ј) containing the NF-B binding motif, which was radiolabeled as described previously (28). For the binding reaction, nuclear protein extract (10 g) was incubated in a total volume of 20 l in binding buffer containing 10 mM HEPES, pH 7.5, 5% glycerol, 50 mM KCl, 1 mM dithiothreitol, 1 g of poly(dI-dC), and radiolabeled (about 10,000 cpm) DNA for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Nuclear Factor-κB Activated by Capacitative Ca2+ Entry Enhances Muscarinic Receptor-mediated Soluble Amyloid Precursor Protein (sAPPα) Release in SH-SY5Y Cells

Choi¹,

Kim²,

Roh

et al. 2006

Journal of Biological Chemistry

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G q / 11 protein-coupled muscarinic receptors are known to regulate the release of soluble amyloid precursor protein (sAPP␣) produced by ␣-secretase processing; however, their signaling mechanisms remain to be elucidated. It has been reported that a muscarinic agonist activates nuclear factor (NF)-B, a transcription factor that has been shown to play an important role in the Alzheimer disease brain, and that NF-B activation is regulated by intracellular Ca 2؉ level. In the present study, we investigated whether NF-B activation plays a role in muscarinic receptor-mediated sAPP␣ release enhancement and contributes to a changed capacitative Ca 2؉ entry (CCE), which was suggested to be involved in the muscarinic receptor-mediated stimulation of sAPP␣ release. Muscarinic receptor-mediated NF-B activation was confirmed by observing the translocation of the active subunit The amyloid precursor protein (APP)4 is a transmembrane protein that produces ␤ amyloid (A␤) by proteolytic cleavage in brains of individuals with Alzheimer disease. APP normally undergoes proteolytic cleavage within the A␤ sequence liberating the ␣-secretase-cleaved APP (sAPP␣). Although evidence indicates that sAPP␣ plays important roles in regulating neuronal survival and plasticity, the mechanisms that mediate these biological activities and the regulation of sAPP␣ secretion have not been established. The transcriptional nuclear factor-B (NF-B) responds to a large number of environmental cues, and in the nervous system, it is modulated under physiological and pathological conditions, which include developmental cell death and acute of chronic neurodegenerative disorders (1, 2). It was proposed that NF-B or other B-binding proteins may be involved in a neuroprotective change in gene expression evoked by various cytokines and by secreted APP in neuronal cells, and therefore, may have a positive effect on Alzheimer disease (3-6).The NF-B/Rel family of dimeric transcriptional factors is involved in the immediate early transcription of a large array of genes induced by mitogenic and antiapoptotic pathogen-associated stimuli (7,8). The eukaryotic NF-B/Rel family of eukaryotic transcription factors, which includes p50, p65, c-Rel, RelB, and p52, bind DNA with high specificity and affinity as homo-or heterodimers to mediate a diverse range of biological processes (9 -11). The most common form of NF-B consists of a heterodimer of p50 (NF-B1) and p65 (Rel A) (12-15). In most resting cells, NF-B is retained in the cytoplasm by its association with inhibitor molecules of the IB family (16). The formation of NF-B-IB complex masks the nuclear localization signal sequence in NF-B and thus prevents its nuclear translocation. In response to various stimuli, NF-B dimers are released from cytoplasmic IB proteins by a process involving site-specific phosphorylation of IB by IB kinase, ubiquitination, and subsequent proteolytic degradation via the 26 S proteasome pathway (6,17,18).The induction of NF-B activity is known to be regulated by the intracellular Ca 2ϩ leve...

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Inhibition of NFkB DNA binding activity by glucocorticoids in rat brain

Cited by 63 publications

References 14 publications

An inflammatory review of glucocorticoid actions in the CNS

An inflammatory review of glucocorticoid actions in the CNS

Prednisolone inhibits PDGF-induced nuclear translocation of NF-κB in human pulmonary artery smooth muscle cells

Nuclear Factor-κB Activated by Capacitative Ca2+ Entry Enhances Muscarinic Receptor-mediated Soluble Amyloid Precursor Protein (sAPPα) Release in SH-SY5Y Cells

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