| First Author | Mundhra S | Year | 2018 |
| Journal | Eur J Immunol | Volume | 48 |
| Issue | 4 | Pages | 612-620 |
| PubMed ID | 29436711 | Mgi Jnum | J:261342 |
| Mgi Id | MGI:6151267 | Doi | 10.1002/eji.201747180 |
| Citation | Mundhra S, et al. (2018) Evidence for dispensability of protein kinase R in host control of tuberculosis. Eur J Immunol 48(4):612-620 |
| abstractText | Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon-gamma (IFNgamma) 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-gamma-dependent macrophage activation (Wu et al. PloS One. 2012 7:e30512). Here we show that co-treatment with IFN-gamma 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-alpha) and less interleukin 10 (IL-10) than seen with IFN-gamma 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-gamma were greater than those of C57BL/6J macrophages, PKR was not required to mediate the IFN-gamma-dependent production of IL-10, RNI or TNF-alpha in either strain. Together the data cast doubt on PKR as a potential therapeutic target for tuberculosis. |
