Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent

Biochem Pharmacol. 2014 Nov 15;92(2):326-35. doi: 10.1016/j.bcp.2014.08.016. Epub 2014 Aug 27.


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-γ)-induced CerS6 upregulation was amplified by 17ß-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-α). Accordingly, CerS6 and TNF-α 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-α and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-α, 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-α/TNFR2.

Keywords: 17ß-estradiol; Ceramide synthase 6; Experimental autoimmune encephalomyelitis; Interferon gamma; Multiple sclerosis; Tumor necrosis factor alpha receptor 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Encephalomyelitis, Autoimmune, Experimental / enzymology*
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Female
  • Humans
  • Male
  • Mice
  • Sex Characteristics*
  • Sphingosine N-Acyltransferase / biosynthesis*


  • CERS6 protein, mouse
  • Sphingosine N-Acyltransferase