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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Väisänen, Sami Gynther, Petra Carlberg, Carsten Toropainen, Sari Matilainen, Juha M. Seuter, Sabine |
| Description | Author Affiliation: Gynther P ( Department of Biosciences, University of Eastern Finland, FI-70211 Kuopio, Finland.) |
| Abstract | Interleukin 12 (IL-12) is a heterodimeric, pro-inflammatory cytokine that plays a central role in activation and differentiation of CD4 $^{+}$ T cells into interferon-γ secreting T-helper type 1 cells. IL-12B , a gene encoding the larger subunit of active IL-12, has been reported to be down-regulated by the nuclear hormone 1α,25-dihydroxyvitamin D $_{3}$ (1α,25(OH) $_{2}$ D $_{3}$ ), but the mechanism of the regulation is unknown. In this study, we have examined the molecular mechanism of transcriptional regulation of the IL-12B gene by 1α,25(OH) $_{2}$ D $_{3}$ in lipopolysaccharide (LPS)-treated human monocytes (THP-1). Quantitative RT-PCR showed that IL-12B mRNA displays a cyclical expression profile and is down-regulated 2.8-fold during the first 8 h and even 12.1-fold 24 h after exposure to 1α,25(OH) $_{2}$ D $_{3}$ . Gel shift and quantitative chromatin immunoprecipitation (ChIP) assays demonstrated vitamin D receptor (VDR) binding to genomic regions 480 and 6300 bp upstream of the IL-12B transcription start site (TSS). Quantitative ChIP assays also revealed that together with VDR and its partner RXR the above regions recruited the co-repressor NCOR2/SMRT and histone deacetylase 3 leading to a decreased histone 4 acetylation and increased histone 3 trimethylation at the IL-12B promoter and its TSS. We suggest that these repressive epigenetic changes eventually cause down-regulation of IL-12 expression. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 5 |
| Volume Number | 1813 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2011-05-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Interleukin-12 Subunit P40 Genetics Vitamin D Analogs & Derivatives Cell Line Chromatin Immunoprecipitation Computational Biology Epigenesis, Genetic Drug Effects Gene Expression Profiling Genome, Human Metabolism Ligands Molecular Sequence Data Protein Multimerization Receptors, Calcitriol Repressor Proteins Response Elements Retinoid X Receptors Toll-Like Receptor 4 Transcription Initiation Site Pharmacology Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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