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

Leonard B. Maggi, Monique R. Heitmeier, Donalyn Scheuner, Randal J. Kaufman, R. Mark L. Buller, John A. Corbett

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish
Pages (from-to)3630-3638
Number of pages9
JournalEMBO Journal
Volume19
Issue number14
DOIs
StatePublished - Jul 17 2000

Keywords

  • IFN-γ
  • Macrophage
  • PKR
  • dsRNA

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