Protein Kinase R as Mediator of the Effects of Interferon (IFN) γ and Tumor Necrosis Factor (TNF) α on Normal and Dysplastic Hematopoiesis

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 hematopoi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-08, Vol.286 (31), p.27506-27514
Main Authors: Sharma, Bhumika, Altman, Jessica K., Goussetis, Dennis J., Verma, Amit K., Platanias, Leonidas C.
Format: Article
Language:English
Subjects:
Antiviral Agents
Base Sequence
Cytokine
DNA Primers
Hematopoiesis
Hematopoiesis - physiology
Humans
Interferon
Interferon-gamma - physiology
Phosphorylation
Protein Kinase R (PKR)
Protein Kinases - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Necrosis Factor-alpha - physiology
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.238501