| First Author | Tanner DC | Year | 2015 |
| Journal | Cell Death Differ | Volume | 22 |
| Issue | 9 | Pages | 1489-501 |
| PubMed ID | 25633192 | Mgi Jnum | J:258960 |
| Mgi Id | MGI:6140292 | Doi | 10.1038/cdd.2014.237 |
| Citation | Tanner DC, et al. (2015) cFLIP is critical for oligodendrocyte protection from inflammation. Cell Death Differ 22(9):1489-501 |
| abstractText | Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNgamma) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFalpha)-induced cytotoxicity. IFNgamma protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-kappaB activation. Although NF-kappaB activation also occurred transiently in the absence of IFNgamma and presence of TNFalpha, this activation was not sufficient to prevent induction of the TNFalpha-responsive cell death pathway. Genetic inhibition of NF-kappaB translocation to the nucleus abrogated IFNgamma-mediated protection and did not change the cell death induced by TNFalpha, suggesting that NF-kappaB activation via IFNgamma induces a different set of responses than activation of NF-kappaB via TNFalpha. A promising candidate is the NF-kappaB target cFLIP (cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNgamma-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFalpha and short hairpin RNA knockdown of cFLIP-abrogated IFNgamma -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNgamma-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFalpha-induced cell death. |
