Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis.

Hdl Handle:
http://hdl.handle.net/10147/254746
Title:
Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis.
Authors:
Aherne, Carol M; McMorrow, Jason; Kane, David; FitzGerald, Oliver; Mix, Kimberlee S; Murphy, Evelyn P
Affiliation:
College of Life Sciences, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.
Citation:
Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. 2009, 46 (16):3345-57 Mol. Immunol.
Journal:
Molecular immunology
Issue Date:
Oct-2009
URI:
http://hdl.handle.net/10147/254746
DOI:
10.1016/j.molimm.2009.07.019
PubMed ID:
19732956
Abstract:
Expression 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.
Item Type:
Article
Language:
en
MeSH:
Active Transport, Cell Nucleus; Arthritis; Cell Nucleus; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Interleukin-8; Male; Nuclear Receptor Subfamily 4, Group A, Member 2; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction; Synovial Membrane; Transcription Factor RelA; Transcription Factors; Tumor Necrosis Factor-alpha
ISSN:
1872-9142

Full metadata record

DC FieldValue Language
dc.contributor.authorAherne, Carol Men_GB
dc.contributor.authorMcMorrow, Jasonen_GB
dc.contributor.authorKane, Daviden_GB
dc.contributor.authorFitzGerald, Oliveren_GB
dc.contributor.authorMix, Kimberlee Sen_GB
dc.contributor.authorMurphy, Evelyn Pen_GB
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.en_GB
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

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