Evidence for dispensability of protein kinase R in host control of tuberculosis

Eur J Immunol. 2018 Apr;48(4):612-620. doi: 10.1002/eji.201747180. Epub 2018 Feb 28.


Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon-γ (IFNγ) and to reduce the burden of Mycobacterium tuberculosis (Mtb) in vivo (Wu et al. PloS One. 2012 7:e30512). Consistent with this, treatment of wild-type (WT) macrophages in vitro with a novel PKR inhibitor (Bryk et al., Bioorg. Med. Chem. Lett. 2011 21:4108-4114) also enhanced IFN-γ-dependent macrophage activation (Wu et al. PloS One. 2012 7:e30512). Here we show that co-treatment with IFN-γ and a new PKR inhibitor identified herein to be highly but not completely selective likewise induced macrophages to produce more reactive nitrogen intermediates (RNI) and tumor necrosis factor alpha (TNF-α) and less interleukin 10 (IL-10) than seen with IFN-γ alone. Unexpectedly, however, this new PKR inhibitor had a comparable effect on PKR-deficient macrophages. Retrospective investigation revealed that the PKR-deficient mice in (Wu et al. PloS One. 2012 7:e30512) had not been backcrossed. On comparing genetically matched PKR-deficient and WT mice, we saw no impact of PKR deficiency on macrophage activation in vitro or during the course of Mtb infection in vivo. In addition, although 129S1/SvImJ macrophage responses to IFN-γ were greater than those of C57BL/6J macrophages, PKR was not required to mediate the IFN-γ-dependent production of IL-10, RNI or TNF-α in either strain. Together the data cast doubt on PKR as a potential therapeutic target for tuberculosis.

Keywords: IFN-γ; Macrophage; PKR; TNF-α; Tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / biosynthesis
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology*
  • Reactive Nitrogen Species / biosynthesis
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • eIF-2 Kinase / antagonists & inhibitors*
  • eIF-2 Kinase / genetics


  • IFNG protein, mouse
  • IL10 protein, mouse
  • Reactive Nitrogen Species
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma
  • eIF-2 Kinase
  • protein kinase R, mouse