Interferon-γ Activates Nuclear Factor-κ B in Oligodendrocytes through a Process Mediated by the Unfolded Protein Response

Our previous studies have demonstrated that the effects of the immune cytokine interferon-gamma (IFN-gamma) in immune-mediated demyelinating diseases are mediated, at least in part, by the unfolded protein response (UPR) in oligodendrocytes. Data indicate that some biological effects of IFN-gamma are elicited through activation of the transcription factor nuclear factor-kappa B (NF-kappa B). Interestingly, it has been shown that activation of the pancreatic endoplasmic reticulum kinase (PERK) branch of the UPR triggers NF-kappa B activation. In this study, we showed that IFN-gamma-induced NF-kappa B activation was associated with activation of PERK signaling in the oligodendroglial cell line Oli-neu. We further demonstrated that blockage of PERK signaling diminished IFN-gamma-induced NF-kappa B activation in Oli-neu cells. Importantly, we showed that NF-kappa B activation in oligodendrocytes correlated with activation of PERK signaling in transgenic mice that ectopically express IFN-gamma in the central nervous system (CNS), and that enhancing IFN-gamma-induced activation of PERK signaling further increased NF-kappa B activation in oligodendrocytes. Additionally, we showed that suppression of the NF-kappa B pathway rendered Oli-neu cells susceptible to the cytotoxicity of IFN-gamma, reactive oxygen species, and reactive nitrogen species. Our results indicate that the UPR is involved in IFN-gamma-induced NF-kappa B activation in oligodendrocytes and suggest that NF-kappa B activation by IFN-gamma represents one mechanism by which IFN-gamma exerts its effects on oligodendrocytes in immune-mediated demyelinating diseases.