期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 48, 期 4, 页码 612-620出版社
WILEY
DOI: 10.1002/eji.201747180
关键词
IFN-gamma; Macrophage; PKR; TNF-alpha; Tuberculosis
类别
资金
- NIAID [AI105807]
- Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine
- William Randolph Hearst Trust
Genetic deficiency of protein kinase R (PKR) in mice was reported to enhance macrophage activation in vitro in response to interferon- (IFN) and to reduce the burden of Mycobacterium tuberculosis (Mtb) in vivo (Wu etal. PloS One. 2012 7:e30512). Consistent with this, treatment of wild-type (WT) macrophages in vitro with a novel PKR inhibitor (Bryk etal., Bioorg. Med. Chem. Lett. 2011 21:4108-4114) also enhanced IFN--dependent macrophage activation (Wu etal. PloS One. 2012 7:e30512). Here we show that co-treatment with IFN- 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-) and less interleukin 10 (IL-10) than seen with IFN- 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 etal. 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- were greater than those of C57BL/6J macrophages, PKR was not required to mediate the IFN--dependent production of IL-10, RNI or TNF- in either strain. Together the data cast doubt on PKR as a potential therapeutic target for tuberculosis.
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