Journal of Biological Chemistry
Volume 286, Issue 31, 5 August 2011, Pages 27506-27514
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Signal Transduction
Protein Kinase R as Mediator of the Effects of Interferon (IFN) γ and Tumor Necrosis Factor (TNF) α on Normal and Dysplastic Hematopoiesis*

https://doi.org/10.1074/jbc.M111.238501Get rights and content
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IFNγ and TNFα are potent inhibitors of hematopoiesis and have been implicated in the pathophysiology of bone marrow failure and myelodysplastic syndromes (MDS). We examined the role of protein kinase R (PKR) in the generation of the inhibitory effects of these myelosuppressive cytokines on hematopoiesis. Our data demonstrate that PKR is rapidly phosphorylated/activated in response to engagement of IFNγ or TNFα receptors in normal human hematopoietic progenitors. Such engagement of PKR is important for the suppressive effects of these cytokines on normal hematopoiesis. Pharmacological targeting of PKR using a specific inhibitor or siRNA-mediated PKR knockdown results in partial reversal of the suppressive effects of IFNγ and TNFα on normal human CD34+-derived myeloid (colony-forming unit-granulocyte-monocytic) and erythroid (burst-forming unit-erythroid) progenitors. Importantly, inhibition of PKR activity or expression increases hematopoietic colony formation from human MDS progenitors, suggesting that drugs that target PKR may provide a novel approach for the treatment of MDS and marrow failure syndromes. Altogether, our data establish that beyond its key role in the induction of IFN-antiviral responses, PKR plays important roles in signaling for IFNγ and other myelosuppressive cytokine receptors as a common mediator of signals for hematopoietic suppression.

Antiviral Agents
Cytokine
Hematopoiesis
Interferon
Signal Transduction
Protein Kinase R (PKR)

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*

This work was supported, in whole or in part, by National Institutes of Health Grants CA77816, CA121192, and AG029138. This work was also supported by a merit review grant from the Department of Veterans Affairs.