| First Author | Schiffmann S | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 11 | Pages | 5723-33 |
| PubMed ID | 22544924 | Mgi Jnum | J:188736 |
| Mgi Id | MGI:5441676 | Doi | 10.4049/jimmunol.1103109 |
| Citation | Schiffmann S, et al. (2012) Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. J Immunol 188(11):5723-33 |
| abstractText | Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C(16:0)-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C(16:0)-Cer levels were increased 1.9-fold in cerebrospinal fluid of MS patients. NO and TNF-alpha secreted by IFN-gamma-activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-gamma-mediated expression of inducible NO synthase (iNOS)/TNF-alpha and NO/TNF-alpha release depends on upregulation of CerS6/C(16:0)-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C(16:0)-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF-alpha release, respectively. EAE/IFN-gamma knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C(16:0)-Cer, iNOS, and TNF-alpha compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C(16:0)-Cer and iNOS/TNF-alpha expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-alpha synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development. |
