Potential role of PKR in double-stranded RNA-induced macrophage activation. EMBO J 2000 Jul 17;19(14):3630-8
Date
07/19/2000Pubmed ID
10899117Pubmed Central ID
PMC313973DOI
10.1093/emboj/19.14.3630Scopus ID
2-s2.0-0034679589 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
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)-1alpha and IL-1beta 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)-kappaB 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 IkappaB degradation or NF-kappaB nuclear localization. The inhibitory actions of dnPKR on dsRNA-induced macrophage activation can be overcome by treatment with interferon (IFN)-gamma, an event associated with PKR degradation. Furthermore, dsRNA + IFN-gamma stimulate inducible nitric oxide synthase expression, IkappaB degradation and NF-kappaB nuclear localization to similar levels in macrophages isolated from PKR(-/-) and PKR(+/+) mice. These findings indicate that both NF-kappaB and PKR are required for dsRNA-induced macrophage activation; however, dsRNA-induced NF-kappaB activation occurs by PKR-independent mechanisms in macrophages. In addition, the PKR dependence of dsRNA-induced macrophage activation can be overcome by IFN-gamma.
Author List
Maggi LB Jr, Heitmeier MR, Scheuner D, Kaufman RJ, Buller RM, Corbett JAAuthor
John A. Corbett PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Cells, Cultured
Enzyme Induction
I-kappa B Proteins
Interferon-gamma
Interleukin-1
Macrophage Activation
Macrophages, Peritoneal
Mice
Mice, Knockout
Mutation
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Poly I-C
RNA, Double-Stranded
RNA, Messenger
Signal Transduction
eIF-2 Kinase
