Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis.
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Affiliation
College of Life Sciences, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland.Issue Date
2009-10MeSH
Active Transport, Cell NucleusArthritis
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
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Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. 2009, 46 (16):3345-57 Mol. Immunol.Journal
Molecular immunologyDOI
10.1016/j.molimm.2009.07.019PubMed ID
19732956Abstract
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
ArticleLanguage
enISSN
1872-9142ae974a485f413a2113503eed53cd6c53
10.1016/j.molimm.2009.07.019
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