期刊
JOURNAL OF LIPID RESEARCH
卷 57, 期 11, 页码 2028-2039出版社
ELSEVIER
DOI: 10.1194/jlr.M070664
关键词
cell signaling; vesicles; lipidomics; multiple sclerosis; oligodendrocyte; sphingolipids
资金
- Foundation for the National Institutes of Health [5P30GM103339-03]
- Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]
- Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE [P20 RR017677]
- COBRE in Lipidomics and Pathobiology at the Medical University of South Carolina [5P30GM103339-03]
- Multiple Sclerosis International Federation (Du Pre Grant)
- National Science Centre, Krakow, Poland [UMO-2013/08/M/NZ3/01040]
Th1 pro-inflammatory cytokines, i.e., TNF- and IFN-, in combination are known to induce cell death in several cell types, including oligodendrocytes, but the mechanism of their synergistic cytotoxicity is unclear. Although ceramide (Cer) has been implicated in cytokine- and stress-induced cell death, its intracellular levels alone cannot explain cytokine synergy. We considered the possibility that Cer released as part of extracellular vesicles may contribute to cytokine-induced synergistic cell death. Using a human oligodendroglioma (HOG) cell line as a model, here we show that exosomes derived from TNF--treated donor cells, while being mildly toxic to fresh cultures (similar to individual cytokines), induce enhanced cell death when added to IFN--primed target cultures in a fashion resembling the effect of cytokine combination. Further, the sphingolipid profiles of secreted exosomes, as determined by HPLC-MS/MS, revealed that the treatment with the cytokines time-dependently induced the formation and exosomal release, in particular of C16-, C24-, and C24:1-Cer species; C16-, C24-, and C24:1-dihydroCer species; and C16-, C24-, and C24:1-SM species. Finally, exogenous C6-Cer or C16-Cer mimicked and enhanced the cytotoxic effects of the cytokines upon HOG cells, thereby supporting the cell death-signaling role of extracellular Cer.
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