Protein kinase R as mediator of the effects of interferon (IFN) γ and tumor necrosis factor (TNF) α on normal and dysplastic hematopoiesis

Bhumika Sharma, Jessica K. Altman, Dennis J. Goussetis, Amit K. Verma, Leonidas C. Platanias

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 IFNγand other myelosuppressive cytokine receptors as a common mediator of signals for hematopoietic suppression.

Original languageEnglish (US)
Pages (from-to)27506-27514
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number31
DOIs
StatePublished - Aug 5 2011

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Hematopoiesis
Protein Kinases
Interferons
Tumor Necrosis Factor-alpha
Myelodysplastic Syndromes
Cytokines
Cohort Effect
Erythroid Precursor Cells
Cytokine Receptors
Tumor Necrosis Factor Receptors
Granulocytes
Small Interfering RNA
Antiviral Agents
Bone
Stem Cells
Bone Marrow
Pharmacology
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Protein kinase R as mediator of the effects of interferon (IFN) γ and tumor necrosis factor (TNF) α on normal and dysplastic hematopoiesis. / Sharma, Bhumika; Altman, Jessica K.; Goussetis, Dennis J.; Verma, Amit K.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 286, No. 31, 05.08.2011, p. 27506-27514.

Research output: Contribution to journalArticle

Sharma, Bhumika ; Altman, Jessica K. ; Goussetis, Dennis J. ; Verma, Amit K. ; Platanias, Leonidas C. / Protein kinase R as mediator of the effects of interferon (IFN) γ and tumor necrosis factor (TNF) α on normal and dysplastic hematopoiesis. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 31. pp. 27506-27514.
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