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dc.contributor.authorAherne, Carol M
dc.contributor.authorMcMorrow, Jason
dc.contributor.authorKane, David
dc.contributor.authorFitzGerald, Oliver
dc.contributor.authorMix, Kimberlee S
dc.contributor.authorMurphy, Evelyn P
dc.date.accessioned2012-12-06T11:36:36Z
dc.date.available2012-12-06T11:36:36Z
dc.date.issued2009-10
dc.identifier.citationIdentification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. 2009, 46 (16):3345-57 Mol. Immunol.en_GB
dc.identifier.issn1872-9142
dc.identifier.pmid19732956
dc.identifier.doi10.1016/j.molimm.2009.07.019
dc.identifier.urihttp://hdl.handle.net/10147/254746
dc.description.abstractExpression of the orphan nuclear receptor NR4A2 is controlled by pro-inflammatory mediators, suggesting that NR4A2 may contribute to pathological processes in the inflammatory lesion. This study identifies the chemoattractant protein, interleukin 8 (IL-8/CXCL8), as a molecular target of NR4A2 in human inflammatory arthritis and examines the mechanism through which NR4A2 modulates IL-8 expression. In TNF-alpha-activated human synoviocyte cells, enhanced expression of IL-8 mRNA and protein correspond to temporal changes in NR4A2 transcription and nuclear distribution. Ectopic expression of NR4A2 leads to robust changes in endogenous IL-8 mRNA levels and co-treatment with TNF-alpha results in significant (p<0.001) secretion of IL-8 protein. Transcriptional effects of NR4A2 on the human IL-8 promoter are enhanced in the presence of TNF-alpha, suggesting molecular crosstalk between TNF-alpha signalling and NR4A2. A dominant negative IkappaB kinase antagonizes the combined effects of NR4A2 and TNF-alpha on IL-8 promoter activity. Co-expression of NR4A2 and the p65 subunit of NF-kappaB enhances IL-8 transcription and functional studies indicate that transactivation occurs independently of NR4A2 binding to DNA or heterodimerization with additional nuclear receptors. The IL-8 minimal promoter region is sufficient to support NR4A2 and NF-kappaB/p65 co-operative activity and NR4A2 can interact with NF-kappaB/p65 on a 39bp sequence within this region. In patients treated with methotrexate for active inflammatory arthritis, a reduction in NR4A2 synovial tissue levels correlate significantly (n=10, r=0.73, p=0.002) with changes in IL-8 expression. Collectively, these data delineate an important role for NR4A2 in modulating IL-8 expression and reveal novel transcriptional responses to TNF-alpha in human inflammatory joint disease.
dc.language.isoenen
dc.rightsArchived with thanks to Molecular immunologyen_GB
dc.subject.meshActive Transport, Cell Nucleus
dc.subject.meshArthritis
dc.subject.meshCell Nucleus
dc.subject.meshDNA-Binding Proteins
dc.subject.meshFemale
dc.subject.meshGene Expression Regulation
dc.subject.meshHumans
dc.subject.meshInterleukin-8
dc.subject.meshMale
dc.subject.meshNuclear Receptor Subfamily 4, Group A, Member 2
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshRNA, Messenger
dc.subject.meshSignal Transduction
dc.subject.meshSynovial Membrane
dc.subject.meshTranscription Factor RelA
dc.subject.meshTranscription Factors
dc.subject.meshTumor Necrosis Factor-alpha
dc.titleIdentification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis.en_GB
dc.typeArticleen
dc.contributor.departmentCollege of Life Sciences, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.en_GB
dc.identifier.journalMolecular immunologyen_GB
dc.description.provinceLeinsteren
html.description.abstractExpression of the orphan nuclear receptor NR4A2 is controlled by pro-inflammatory mediators, suggesting that NR4A2 may contribute to pathological processes in the inflammatory lesion. This study identifies the chemoattractant protein, interleukin 8 (IL-8/CXCL8), as a molecular target of NR4A2 in human inflammatory arthritis and examines the mechanism through which NR4A2 modulates IL-8 expression. In TNF-alpha-activated human synoviocyte cells, enhanced expression of IL-8 mRNA and protein correspond to temporal changes in NR4A2 transcription and nuclear distribution. Ectopic expression of NR4A2 leads to robust changes in endogenous IL-8 mRNA levels and co-treatment with TNF-alpha results in significant (p<0.001) secretion of IL-8 protein. Transcriptional effects of NR4A2 on the human IL-8 promoter are enhanced in the presence of TNF-alpha, suggesting molecular crosstalk between TNF-alpha signalling and NR4A2. A dominant negative IkappaB kinase antagonizes the combined effects of NR4A2 and TNF-alpha on IL-8 promoter activity. Co-expression of NR4A2 and the p65 subunit of NF-kappaB enhances IL-8 transcription and functional studies indicate that transactivation occurs independently of NR4A2 binding to DNA or heterodimerization with additional nuclear receptors. The IL-8 minimal promoter region is sufficient to support NR4A2 and NF-kappaB/p65 co-operative activity and NR4A2 can interact with NF-kappaB/p65 on a 39bp sequence within this region. In patients treated with methotrexate for active inflammatory arthritis, a reduction in NR4A2 synovial tissue levels correlate significantly (n=10, r=0.73, p=0.002) with changes in IL-8 expression. Collectively, these data delineate an important role for NR4A2 in modulating IL-8 expression and reveal novel transcriptional responses to TNF-alpha in human inflammatory joint disease.


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