Bcl‐3 is an interleukin‐1–responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene

Elliott, Sarah; Coon, Charles I.; Hays, Ezra; Stadheim, Terrance A.; Vincenti, Matthew P.

doi:10.1002/art.10675

Cited by 54 publications

(44 citation statements)

References 33 publications

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“…As a result, activity of NF-κB was decreased in IL-1β-stimulated EGCG-treated IVD cells. This effect was observed after 1 h, since NF-κB is a protein complex that functions as a "rapid-acting" transcription factor and as such regulates the transcription of more than 150 genes related to stress responses, including MMPs (Elliott et al, 2002;Liacini et al, 2003;Mengshol et al, 2000;Wuertz et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The development of back pain involves both nociceptive and neuropathic pathophysiological mechanisms (Forster et al, 2013;Morlion, 2011), with IVD degeneration being one of the major underlying causes. IVD degeneration is induced by phenotypic changes in the NP cells, leading to tissue degradation , as well as to promotion of neoinnervation of the disc and hence the transmission of pain in vivo (Alimasi et al, 2013;Richardson et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Epigallocatechin 3-gallate suppresses interleukin-1β-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats

Krupková¹,

Sekiguchi²,

Klasen³

et al. 2014

eCM

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Intervertebral disc (IVD) disease, which is characterised by age-related changes in the adult disc, is the most common cause of disc failure and low back pain. The purpose of this study was to analyse the potential of the biologically active polyphenol epigallocatechin 3-gallate (EGCG) for the treatment of painful IVD disease by identifying and explaining its anti-inflammatory and anti-catabolic activity. Human IVD cells were isolated from patients undergoing surgery due to degenerative disc disease (n = 34) and cultured in 2D or 3D. An inflammatory response was activated by IL-1, EGCG was added, and the expression/activity of inflammatory mediators and pathways was measured by qRT-PCR, western blotting, ELISA, immunofluorescence and transcription factor assay. The small molecule inhibitor SB203580 was used to investigate the involvement of the p38 pathway in the observed effects. The analgesic properties of EGCG were analysed by the von Frey filament test in Sprague-Dawley rats (n = 60). EGCG significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-B. AbstractIntervertebral disc (IVD) disease, which is characterised by age-related changes in the adult disc, is the most common cause of disc failure and low back pain. The purpose of this study was to analyse the potential of the biologically active polyphenol epigallocatechin 3-gallate (EGCG) for the treatment of painful IVD disease by identifying and explaining its anti-inflammatory and anti-catabolic activity. Human IVD cells were isolated from patients undergoing surgery due to degenerative disc disease (n = 34) and cultured in 2D or 3D. An inflammatory response was activated by IL-1β, EGCG was added, and the expression/activity of inflammatory mediators and pathways was measured by qRT-PCR, western blotting, ELISA, immunofluorescence and transcription factor assay. The small molecule inhibitor SB203580 was used to investigate the involvement of the p38 pathway in the observed effects. The analgesic properties of EGCG were analysed by the von Frey filament test in SpragueDawley rats (n = 60). EGCG significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-κB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigallocatechin 3-gallate suppresses interleukin-1β-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats

Krupková¹,

Sekiguchi²,

Klasen³

et al. 2014

eCM

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“…Thus, LPS up-regulates it in B cells (27), TNF-␣ in hepatocytes (21), and IL-1 in chondrocytes and synovial cells (28). Further evidence will be required to determine whether these stimuli act through the B site in HS3.…”

Section: Discussionmentioning

confidence: 99%

NF-κB RegulatesBCL3Transcription in T Lymphocytes Through an Intronic Enhancer

Ge¹,

Li²,

Wilder

et al. 2003

The Journal of Immunology

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Exposure to soluble protein Ags in vivo leads to abortive proliferation of responding T cells. In the absence of a danger signal, artificially provided by adjuvants, most responding cells die, and the remainder typically become anergic. The adjuvant-derived signals provided to T cells are poorly understood, but recent work has identified BCL3 as the gene, of those tested, with the greatest differential transcriptional response to adjuvant administration in vivo. As an initial step in analyzing transcriptional responses of BCL3 in T cells, we have identified candidate regulatory regions within the locus through their evolutionary conservation and by analysis of DNase hypersensitivity. An evolutionarily conserved DNase hypersensitive site (HS3) within intron 2 was found to act as a transcriptional enhancer in response to stimuli that mimic TCR activation, namely, PHA and PMA. In luciferase reporter gene constructs transiently transfected into the Jurkat T cell line, the HS3 enhancer can cooperate not only with the BCL3 promoter, but also with an exogenous promoter from herpes simplex thymidine kinase. Deletional analysis revealed that a minimal sequence of ∼81 bp is required for full enhancer activity. At the 5′ end of this minimal sequence is a κB site, as confirmed by EMSAs. Mutation of this site in the context of the full-length HS3 abolished enhancer activity. Cotransfection with NF-κB p65 expression constructs dramatically increased luciferase activity, even without stimulation. Conversely, cotransfection with the NF-κB inhibitor IκBα reduced activation. Together, these results demonstrate a critical role for NF-κB in BCL3 transcriptional up-regulation by TCR-mimetic signals.

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“…Quantitative Real-time Reverse Transcription-PCR mRNA levels were assayed by quantitative real-time reverse transcription-PCR as described previously (29,30). The primers used to detect MMP-1, MMP-3, MMP-10, and glyceraldehyde-3-phosphate dehydrogenase were purchased from SA Biosciences.…”

Section: Western Blot Analysismentioning

confidence: 99%

CCAAT Enhancer Binding Protein-β Regulates Matrix Metalloproteinase-1 Expression in Interleukin-1β–Stimulated A549 Lung Carcinoma Cells

Armstrong¹,

Phelps²,

Vincenti³

2009

Molecular Cancer Research

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Matrix metalloproteinase-1 (MMP-1) is an inflammationinducible neutral protease that mediates extracellular matrix remodeling and promotes tumor invasion. In this study, we examined the activation of MMP-1 gene expression in A549 lung carcinoma cells stimulated with the inflammatory cytokine interleukin-1β (IL-1β). We found that MMP-1 mRNA levels were maximal following 16 hours of IL-1β stimulation and that this correlated with the expression of the transcription factor CCAAT enhancer-binding protein-β (CEBPB). Knockdown of CEBPB expression with short hairpin RNA abrogated the expression of MMP-1, MMP-3, and MMP-10 in IL-1β-stimulated A549 cells. An established CEBP element in the MMP-1 promoter was found to be required for basal and IL-1β-induced transcription. Electrophoresis mobility shift assays showed that CEBPB binds to this promoter element maximally 16 hours after IL-1β stimulation. DNA affinity chromatography studies showed that the LAP1, LAP2, and LIP isoforms of CEBPB bind to the IL-1β-responsive CEBPB site in the MMP-1 promoter. Exogenous expression of the LAP1 and LAP2 isoforms stimulated the MMP-1 promoter, whereas LIP had no effect. Phosphorylation of CEBPB at Thr 235 peaked at 16 hours in IL-1β-stimulated cells. The MEK inhibitor U0126 inhibited this phosphorylation and reduced MMP-1 gene induction. These studies establish CEBPB as an important mediator of metalloproteinase gene activation during inflammatory responses in lung cancer cells and highlight the different regulatory roles of CEBPB isoforms. (Mol Cancer Res 2009;7(9):1517-24)

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Bcl‐3 is an interleukin‐1–responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene

Cited by 54 publications

References 33 publications

Epigallocatechin 3-gallate suppresses interleukin-1β-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats

Epigallocatechin 3-gallate suppresses interleukin-1β-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats

NF-κB RegulatesBCL3Transcription in T Lymphocytes Through an Intronic Enhancer

CCAAT Enhancer Binding Protein-β Regulates Matrix Metalloproteinase-1 Expression in Interleukin-1β–Stimulated A549 Lung Carcinoma Cells

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