Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts

Davies, Mark; Harding, Christine J; Raines, Stephanie; Tolley, Kurt P.; Parker, Andrew E.; Downey-Jones, Mark; Needham, Maurice

doi:10.1186/1476-9255-2-15

Cited by 33 publications

(23 citation statements)

References 42 publications

(44 reference statements)

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“…Previous studies have suggested a role for the NR4A receptors in inflammatory joint disease, and these receptors have been documented in synovial tissue and bone (32)(33)(34)(35)(36)(37). However, few target genes have been identified in these tissues (35,38,39), and the function of these receptors within joints remains elusive. Our study is the first to document NR4A receptor expression in cartilage and chondrocytes, the principal cell type present in articular cartilage.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, osteopontin is induced by NURR1 in osteoblasts (38), and osteopontin may inhibit inflammation in cartilage by blocking some of the effects of IL-1␤ (41). Within synoviocytes, NURR1 induces expression of IL-8 (35), and this chemokine acts to recruit inflammatory cells and to promote resolution early in synovitis. As additional transcriptional targets of NURR1 are elucidated, therapeutic strategies to modulate this receptor in a tissue-and promoter-selective manner may evolve.…”

Section: Volume 282 • Number 13 • March 30 2007mentioning

confidence: 99%

“…The NURR1 promoter is activated by NFB and cAMP-responsive element-binding protein (CREB) in response to inflammatory signals (33). NURR1 induces expression of the chemokine IL-8 in synoviocytes (35), which may enhance cell migration and resolution during the early stages of inflammatory joint disease. NURR1 has also been documented in bone (36,37), and here, this receptor regulates the expression of genes involved in bone homeostasis, osteopontin and osteocalcin (38,39).…”

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confidence: 99%

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Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage

Mix

Attur

Al-Mussawir

et al. 2007

Journal of Biological Chemistry

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The NR4A orphan receptors (Nur77, NURR1, and NOR-1) are emerging as key regulators of cytokine and growth factor action in chronic inflammatory diseases. In this study, we address the role of these receptors in cartilage homeostasis during inflammatory joint disease. We document for the first time expression of the NR4A receptors in osteoarthritic cartilage. Relative to Nur77 and NOR-1, NURR1 is expressed at the highest level and correlates with cyclooxygenase-2 levels in cartilage. Consistent with this observation, cyclooxygenase-2-derived prostaglandin E 2 (PGE 2 ) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE 2 -mediated processes in cartilage. We demonstrate that PGE 2 represses interleukin-1␤-induced matrix metalloproteinase (MMP)-1 and that transient overexpression of NURR1 is sufficient to antagonize expression of this gene. Furthermore, MMP-1 promoter activity is potently suppressed by NURR1, resulting in a significant reduction in endogenous MMP-1 mRNA and secreted pro-MMP-1 protein. In addition, NURR1 selectively antagonizes cytokine-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2. To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (؊1772 to ؊1546 bp) and that repression does not require consensus binding sites for NURR1. We confirm that NURR1 targets a 40-bp promoter sequence that is also positively regulated by ETS transcription factors. Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter. We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation.Nuclear hormone receptors comprise a large family of tightly regulated transcription factors that play critical roles in normal physiology and disease processes (1). Several of these receptors are activated by ligands such as vitamins and hormones, which cause allosteric changes in the receptors and alter the transcription of target genes. Modulation of these receptors with synthetic ligands has shown great promise in the treatment of cancer and inflammatory diseases (2). In contrast, orphan nuclear receptors control gene expression in the absence of ligands, and elucidating the functions and transcriptional targets of these receptors may also lead to therapeutic advances.The NR4A receptors are a subfamily of orphan nuclear receptors consisting of nerve growth factor-induced clone B (Nur77, NR4A1), NURR1 (nuclear receptor related-1; NR4A2), and NOR-1 (neuron-derived orphan receptor-1; NR4A3) (3). As ligand-independent receptors (4), the activity of these transcription factors is tightly controlled at the level of expression. Nur77, NURR1, and NOR-1 exhibit distinct and overlapping expression patterns in a number of cell and tissue types (3), indicating that these receptors have unique an...

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Section: Discussionmentioning

confidence: 99%

Section: Volume 282 • Number 13 • March 30 2007mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage

Mix

Attur

Al-Mussawir

et al. 2007

Journal of Biological Chemistry

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“…The nuclear orphan receptor, NURR1, was shown to regulate pro-inflammatory mediators [44] and ICAM-1 is a previously described marker of inflammation in Caco-2 cells [45]. Although NURR1 has been previously identified in intestinal carcinoma cells in vivo [46], NURR1 expression has not been previously shown in intestinal cell lines.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone–pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers

Keely

Ryan

Haddleton

et al. 2009

Journal of Controlled Release

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The mucoadhesive polymer, poly(dimethylamino)ethyl methacrylate (pDMAEMA) was synthesised by living radical polymerisation and subsequently conjugated by esterification to the anti-inflammatory corticosteroid, dexamethasone, to separately yield two concentrations of conjugates with ratios of 10:1 and 20:1 active:polymer. The hypothesis was to test whether the active agent maintained in vitro bioactivity when exposed to the apical side of human intestinal epithelial monolayers, Caco-2 and mucous-covered HT29-MTX-E12 (E12). HPLC analysis showed that 80% of the dexamethasone in both conjugates was attached to pDMAEMA. Similar to pDMAEMA, fluorescently-labelled dexamethasone-pDMAEMA conjugates were bioadhesive to Caco-2 and mucoadhesive to E12. Apical addition of conjugates suppressed mRNA expression of the inflammatory markers, NURR1 and ICAM-1 in E12 following stimulation by PGE2 and TNF-α, respectively. Conjugates also suppressed TNF-α stimulated cytokine secretion to the basolateral side of Caco-2 monolayers. pDMAEMA was inactive in these assays. Measurement of dexamethasone permeability from conjugates across monolayers suggested that conjugation reduced permeability compared to free dexamethasone. LDH assay indicated that conjugates were not cytotoxic to monolayers at high concentrations. Anti-inflammatory agents can therefore be successfully conjugated to polymers and they retain adhesion and bioactivity to enable formulation for topical administration.

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“…Activated macrophages have elevated nuclear receptor subfamily 4 (Nurr1, NR4A2) expression und Nurr1 is also higher in visceral fat but over expression of Nurr1 in monocytic cell lines reduces the expression IL-6, CXCL8 and CCL2 and down regulates scavenger receptor-A, CD36, and CD11b [38]. In contrast, over expression of Nurr1 in a synoviocyte cell line leads to increased gene expression of proinflammatory genes like CXCL8 [39]. Additional studies may lead to the identification of the cell type that induces Nurr1, current data though exclude resident macrophages as being responsible for that.…”

Section: Adipose Tissuementioning

confidence: 91%

Does Global Gene Expression Analysis in Type 2 Diabetes Provide an Opportunity to Identify Highly Promising Drug Targets?

Buechler

Schäffler²

2007

EMIDDT

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The recent technological advances in high-throughput gene expression analysis allow the simultaneous investigation of thousands of genes. These technologies represent promising tools for the identification of new drug targets and considerable progress has been achieved in cancer research where microarray data provide a basis to design new drugs and to predict adverse reactions and the efficacy of chemotherapy. The metabolic syndrome represents a cluster of disorders including high blood pressure, insulin resistance/type 2 diabetes mellitus, visceral obesity and dyslipidaemia with fatty liver disease being a common associated complication. High-throughput gene expression analyses using GeneChips, microarrays and serial analysis of gene expression (SAGE) have been applied to study global gene expression in insulin resistance/type 2 diabetes mellitus. Type 2 diabetes mellitus is a multifactorial and polygenic disease by which several organs are affected. Therefore, the identification of both, disease causing and therapeutically relevant target genes is an ambitious challenge. In the present review we focus on genomic approaches that used biopsies from human skeletal muscle, liver and adipose tissue, the main organs affected by insulin resistance. Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators are decreased in skeletal muscle in insulin resistance accounting for the reduced expression of genes involved in mitochondrial oxidative phosphorylation. Hepatic steatosis is also linked to alterations in mitochondrial phosphorylation and oxidative metabolism. An up regulation of pro-inflammatory genes can be detected in early stages of fatty liver disease without histological signs of inflammation. Impaired adipogenesis, intra-adipose accumulation of macrophages and a sustained release of inflammatory and acute phase proteins are characteristic features of adipose tissue in obesity and may aggravate systemic insulin resistance.

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Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts

Cited by 33 publications

References 42 publications

Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage

Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage

Dexamethasone–pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers

Does Global Gene Expression Analysis in Type 2 Diabetes Provide an Opportunity to Identify Highly Promising Drug Targets?

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