Journal
BIOCHEMICAL PHARMACOLOGY
Volume 92, Issue 2, Pages 326-335Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.08.016
Keywords
Ceramide synthase 6; Experimental autoirnmune; encephalomyelitis; Multiple sclerosis; Tumor necrosis factor alpha receptor 2; Interferon gamma; 17 beta-estradiol
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Funding
- Else Kroner-Fresenius Foundation (EKFS)
- Research Training Group Translational Research Innovation-Pharma (TRIP)
- Landesoffensive zur Entwicklung wissenschaftlich-okonomischer Exzellenz (LOEWE), Schwerpunkt: Anwendungsorientierte Arzneimittelforschung
- German Research Foundation [SFB 645, B2]
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Ceramides (Cer) are mediators of inflammatory processes. In a chronic experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we observed a significant elevation of C16-Cer and its synthesizing enzyme, ceramide synthase(CerS)6, in the lumbar spinal cord. In the present study, we have confirmed that C16-Cer and CerS6 are also upregulated in the lumbar spinal cord in a spontaneous relapse-remitting EAE model, using SJL mice overexpressing a transgenic T cell receptor (TCR1640). CerS6 was found to be expressed in macrophages, T cells and B cells in EAE lesions. In macrophages, we demonstrated that interferon gamma (IFN-gamma)-induced CerS6 upregulation was amplified by 17 beta-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-alpha). Accordingly, CerS6 and TNF-alpha expression was upregulated predominantly in the spinal cord in female TCR1640 mice, which usually develop the relapse-remitting form of EAE, while male TCR1640 mice showed an attenuated regulation of CerS6. and TNF-alpha and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-alpha, which is linked to neuroprotection and remyelination, was also upregulated to a greater extent during EAE in female TCR1640 mice in comparison to male TCR1640 mice. Taken together, our results confirm the upregulation of CerS6 and C16-Cer in an adjuvant-independent, physiological EAE model and further suggest an anti-inflammatory role of CerS6 in the regulation of the disease course in female TCR1640 mice via TNF-alpha/TNFR2. (C) 2014 Elsevier Inc. All rights reserved.
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