Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines

Abstract

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 TNFalpha, 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 TNFalpha had the ability to activate the ERVWE1 promoter through an NF-kappaB-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNFalpha enhances the binding of the p65 subunit of NF-kappaB, to its cognate site within the promoter. The effect of TNFalpha is abolished by siRNA directed against p65. Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNFalpha-mediated induction of syncytin-1 in multiple sclerosis.

Expression of Human Endogenous Retrovirus Type K (HML-2) Is Activated by the Tat Protein of HIV-1

“…Although most HERV genes seem to be nonfunctional, there are some endogenous retroviral genes that are expressed, even becoming important contributors to human physiological processes, as can be seen in trophoblast development (2,34,44,80). However, HERV gene expression appears to be tightly controlled under normal circumstances, and only when cellular fitness or integrity is compromised (e.g., with synthetic chemical agents, radiation, stress, cytokines/chemokines, or biological agents acting upon human cells) is there pronounced or increased expression of endogenous retroviral elements (26,57,62,63,81,121,127). Under conditions where an exogenous virus, such as HIV-1, establishes a productive infection, the repression of HERV expression can be lifted (130).…”

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

“…Recent studies indicate that Syncytin-1 transcript levels are quantitatively increased in the brains of MS patients compared with other inflammatory neurological disease controls (10). Interestingly, TNF-␣, an inflammatory molecule in the brains of MS patients, was found to enhance Syncytin-1 expression in astrocytes (11), which consequently results in production of free radicals and cytokines (12) that could affect expression of ASCT1 and ASCT2, given that free radicals influence expression of membrane proteins (13,14). Free radicals are also produced when cells undergo persistent endoplasmic reticulum (ER) stress (15), a constellation of host responses, which maintain cellular homeostasis, termed the unfolded protein response (16).…”

Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines

“…Most significantly expression of syncytin-1 has also been shown to suppress staurosporin-induced apoptosis in Chinese hamster ovary (CHO) cells (45) Although there is significant evidence for syncytin-1 conferring a growth/survival advantage in malignant cells, there is also evidence that its expression induces demyelination and cell death in oligodendrocytes which is consistent with the protein playing a causative role in neurodegenerative disease (48). Indeed, as previously mentioned, syncytin-1 is thought to play an instrumental role in MS (30,32,49). Thus it is significant that AgNPs are also known to cause neuronal damage (50,51) and we speculate this could be augmented by induction of syncytin-1.…”