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Cytokine. 2013 Jul;63(1):36-42. doi: 10.1016/j.cyto.2013.04.004. Epub 2013 Apr 30.

Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells.

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  • 1F. Widjaja Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract

TL1A/TNFSF15 has been associated with IBD (inflammatory bowel disease) in GWAS (genome-wide association study) and plays a role mediating mucosal inflammation in IBD. Higher TL1A expression is associated with disease severity in both patients and mouse models. Although TL1A has been studied extensively for IBD-associated SNPs, the cis/trans-regulatory regions are poorly defined. Herein we identify response elements regulating TNFSF15 in primary human myeloid cells. Peripheral mononuclear cells transfected with TNFSF15 promoter constructs displayed 30-fold enhanced promoter activity in a minimal -74 bp region. Transactivation was mediated partly by AP-1, since mutation of the AP-1 site resulting in loss of promoter activity. Monocytes transfected with c-Jun siRNA or treated with TAT-TI-JIP (JNK Inhibitor VII TAT-TI-JIP) demonstrated reduced TL1A mRNA and protein levels. Surprisingly, constructs larger than -74 bp did not increase promoter expression (expression of -1275 bp construct was 25% of -74 bp activity), suggesting the presence of both activating and repressing TL1A promoter elements. In fact, mutation of the -210 bp NFκB site enhanced promoter activity (60-fold) suggesting a repressive role for this site. DNA-protein binding to the TL1A AP-1 and NFκB elements was inhibited by excess consensus or TL1A oligonucleotides and binding and confirmed by chromatin immuno-precipitation analysis. Yet, despite the fact that the -210 bp NFκB site acts as a suppressor element, overall mRNA and protein expression were inhibited in monocytes treated with MG132 (NFκB/proteasome inhibitor) or SN50 (NFκB-p50 blocking peptide), suggesting that NFκB acts as both an activator and silencer of TL1A expression. These data suggest that modulation of TL1A expression involves a complex interplay between positive and negative signals, binding to distinct regulatory regions.

Copyright © 2013. Published by Elsevier Ltd.

PMID:
23642711
[PubMed - indexed for MEDLINE]
PMCID:
PMC3889718
Free PMC Article
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