STAT1/IRF-1 Signaling Pathway Mediates the Injurious Effect of Interferon-Gamma on Oligodendrocyte Progenitor Cells

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that is critically involved in the pathogenesis of inflammatory demyelinating diseases. There is strong evidence that IFN-gamma can function as a distinct and independent injurious factor to oligodendrocyte progenitor cells (OPCs). The intracellular signaling pathways leading to OPC death, however, remain poorly understood. In this study, we examined IFN-gamma signaling in OPCs in relation to cell death in. vitro. Using expression knock-down and forced overexpression methods, we directly demonstrated the role of signal transducer and transcription activator 1 (STAT1) and interferon-regulated factor 1 (IRF-1) in IFN-gamma- induced OPC death. In addition, our study identified two proapoptotic genes, caspase 1 and double-stranded RNA-dependent protein kinase (PKR), whose expression was upregulated by IFN-gamma and transcriptionally controlled by IRF-1. The conclusion of this study is that STAT1 and IRF-1 function as components of the signaling pathway that mediates IFN-gamma-induced OPC death. (C) 2009 Wiley-Liss, Inc.