Continuous (24 h) exposure of mixed oligodendrocyte/microglial cells to peptides 45–89 derived from citrullinated C8 isoforms of myelin basic protein (MBP) induces cell death. In contrast, MBP-C8 at the same molecular concentration is not toxic to oligodendrocyte/microglial cells as detected by the MTT test and trypan blue exclusion method. The loss of oligodendrocyte/microglial cells resulted in the release of cytochrome c from mitochondria, suggesting MBP 45–89-induced apoptosis. On the other hand, peptides 45–89 stimulated the secretion of nitric oxide from microglial cells only via induction of iNOS. The addition of peptide 45–89 to the microglial cells led to a decrease of the level of the inhibitory protein IkB, indicating that activation of the transcription factor NF-kB is involved in these processes. We propose that the immunodominant peptide 45–89 induces damage of oligodendrocytes by activation of microglial cells and subsequent generation of nitric oxide, and that this may be the first step in the initiation of autoimmunity
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