Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis.
dc.contributor.author | Aherne, Carol M | |
dc.contributor.author | McMorrow, Jason | |
dc.contributor.author | Kane, David | |
dc.contributor.author | FitzGerald, Oliver | |
dc.contributor.author | Mix, Kimberlee S | |
dc.contributor.author | Murphy, Evelyn P | |
dc.date.accessioned | 2012-12-06T11:36:36Z | |
dc.date.available | 2012-12-06T11:36:36Z | |
dc.date.issued | 2009-10 | |
dc.identifier.citation | Identification 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.issn | 1872-9142 | |
dc.identifier.pmid | 19732956 | |
dc.identifier.doi | 10.1016/j.molimm.2009.07.019 | |
dc.identifier.uri | http://hdl.handle.net/10147/254746 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Molecular immunology | en_GB |
dc.subject.mesh | Active Transport, Cell Nucleus | |
dc.subject.mesh | Arthritis | |
dc.subject.mesh | Cell Nucleus | |
dc.subject.mesh | DNA-Binding Proteins | |
dc.subject.mesh | Female | |
dc.subject.mesh | Gene Expression Regulation | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Interleukin-8 | |
dc.subject.mesh | Male | |
dc.subject.mesh | Nuclear Receptor Subfamily 4, Group A, Member 2 | |
dc.subject.mesh | Promoter Regions, Genetic | |
dc.subject.mesh | RNA, Messenger | |
dc.subject.mesh | Signal Transduction | |
dc.subject.mesh | Synovial Membrane | |
dc.subject.mesh | Transcription Factor RelA | |
dc.subject.mesh | Transcription Factors | |
dc.subject.mesh | Tumor Necrosis Factor-alpha | |
dc.title | Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. | en_GB |
dc.type | Article | en |
dc.contributor.department | College of Life Sciences, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland. | en_GB |
dc.identifier.journal | Molecular immunology | en_GB |
dc.description.province | Leinster | en |
html.description.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. |