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.
Wang
Yan
Y
Rush University Medical Center, Department of Neurological Sciences, Multiple Sclerosis Center, Chicago, Illinois, USA.
Ren
Zhihua
Z
Tao
Duan
D
Tilwalli
Shilpa
S
Goswami
Rajendra
R
Balabanov
Roumen
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D009836:Oligodendroglia / Q000502:physiology*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D007371:Interferon-gamma; D053612:Janus Kinases; D019892:eIF-2 Kinase; D020170:Caspase 1