Potential role of PKR in double-stranded RNA-induced macrophage activation

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Abstract
In this study, the role of the double‐stranded (ds) RNA‐dependent protein kinase (PKR) in macrophage activation was examined. dsRNA [polyinosinic:polycytidylic acid (poly IC)]‐stimulated inducible nitric oxide synthase, interleukin (IL)‐1α and IL‐1β mRNA expression, nitrite formation and IL‐1 release are attenuated in RAW264.7 cells stably expressing dominant negative (dn) mutants of PKR. The transcriptional regulator nuclear factor (NF)‐κB is activated by dsRNA, and appears to be required for dsRNA‐induced macrophage activation. While dnPKR mutants prevent macrophage activation, they fail to attenuate dsRNA‐induced IκB degradation or NF‐κB nuclear localization. The inhibitory actions of dnPKR on dsRNA‐induced macrophage activation can be overcome by treatment with interferon (IFN)‐γ, an event associated with PKR degradation. Furthermore, dsRNA + IFN‐γ stimulate inducible nitric oxide synthase expression, IκB degradation and NF‐κB nuclear localization to similar levels in macrophages isolated from PKR−/− and PKR+/+ mice. These findings indicate that both NF‐κB and PKR are required for dsRNA‐induced macrophage activation; however, dsRNA‐induced NF‐κB activation occurs by PKR‐independent mechanisms in macrophages. In addition, the PKR dependence of dsRNA‐induced macrophage activation can be overcome by IFN‐γ.