Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines
- Section of Microbiology, Department of Biomedical Sciences, Center of Excellence for Biotechnology Development and Biodiversity Research, Sassari (Italy) and Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900N. 12th Street, 015-96, Philadelphia, PA 19122 (United States)
- Section of Microbiology, Department of Biomedical Sciences, Center of Excellence for Biotechnology Development and Biodiversity Research, Sassari (Italy)
- Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900N. 12th Street, 015-96, Philadelphia, PA 19122 (United States)
Syncytin-1 has a physiological role during early pregnancy, as mediator of trophoblast fusion into the syncytiotrophoblast layer, hence allowing embryo implantation. In addition, its expression in nerve tissue has been proposed to contribute to the pathogenesis of multiple sclerosis (MS). Syncytin-1 is the env glycoprotein of the ERVWE1 component of the W family of human endogenous retroviruses (HERV), located on chromosome 7q21-22, in a candidate region for genetic susceptibility to MS. The mechanisms of ERVWE1 regulation in nerve tissue remain to be identified. Since there are correlations between some cytokines and MS outcome, we examined the regulation of the syncytin-1 promoter by MS-related cytokines in human U-87MG astrocytic cells. Using transient transfection assays, we observed that the MS-detrimental cytokines TNF{alpha}, interferon-{gamma}, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-{beta} is inhibitory. The effects of cytokines are reduced by the deletion of the cellular enhancer domain of the promoter that contains binding sites for several transcription factors. In particular, we found that TNF{alpha} had the ability to activate the ERVWE1 promoter through an NF-{kappa}B-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNF{alpha} enhances the binding of the p65 subunit of NF-{kappa}B, to its cognate site within the promoter. The effect of TNF{alpha} is abolished by siRNA directed against p65. Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNF{alpha}-mediated induction of syncytin-1 in multiple sclerosis.
- OSTI ID:
- 20977025
- Journal Information:
- Virology, Vol. 362, Issue 1; Other Information: DOI: 10.1016/j.virol.2006.12.019; PII: S0042-6822(06)00923-8; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0042-6822
- Country of Publication:
- United States
- Language:
- English
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