Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia

Auch, Corey J.; Saha, Ramendra N.; Sheikh, Faruk G.; Liu, Xiaojuan; Jacobs, Bertram L.; Pahan, Kalipada

Environmental factor(s), such as viral infection, has been implicated as one of the triggering events leading to neuroinflammation in multiple sclerosis. This study underlines the importance of double-stranded RNA (dsRNA), the active component of a viral infection, in inducing the expression of inducible nitric oxide synthase (iNOS) in human astroglia. DsRNA in the form of synthetic polyinosinic-polycytidylic acid (poly IC) induced expression of iNOS and iNOS promoter-driven luciferase activity through activation of nuclear factor (NF)-κB and CCAAT/enhancer-binding proteinβ (C/EBPβ). In addition, we show that inhibitors of protein kinase R attenuated iNOS by suppressing the activation of NF-κB but not C/EBPβ. In contrast, knock down of p38 mitogen-activated protein kinase (MAPK) attenuated iNOS by suppressing the activation of C/EBPβ but not NF-κB. This study delineates a novel role of dsRNA in inducing the expression of iNOS through dsRNA-activated protein kinase (PKR)-mediated activation of NF-κB and p38-mediated activation of C/EBPβ in human astroglia that may participate in virus-induced neurological abnormalities.