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Effects of recombinant interferons on human megakaryocyte growth
1Department of Medical Technology, University of Vermont, Burlington 05405.
Abstract:
Interferons (IFNs) have been shown to suppress the proliferation of human pluripotent and single-lineage hematopoietic progenitor cells. Treatments with IFNs have reduced platelet counts in patients with myeloproliferative disorders (MPD) but have not altered platelet counts in patients with healthy marrows. We assessed recombinant alpha and gamma IFN (rIFN-alpha and rIFN-gamma) preparations for their effect on the growth of marrow megakaryocytes (MKs) from normal donors and from patients with MPD. In addition, the interactions of recombinant interleukin 3 (rIL-3) recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM) with the suppressive effects of rIFNs were examined. The addition of rIFN-alpha to liquid cultures resulted in a dose-dependent inhibition of normal marrow and MPD marrow MK growth. Inhibition with rIFN-gamma was only observed in normal marrows at 2500 U/ml and 12,500 U/ml; and rIFN-gamma unexpectedly stimulated MK growth in some culture conditions. Thirty units per milliliter rIL-3 overcame the inhibitory effect of rIFN-alpha on MK growth, but rGM-CSF or 3 U/ml rIL-3 did not. These studies with rIFN-alpha demonstrate that MPD marrow MKs and their precursor cells are no more sensitive to rIFN-alpha than are normal marrow MKs. Clinically, rIFN-gamma would be expected to be less effective than rIFN-alpha at controlling thrombocytosis in patients with MPD.
Insights
Interferons (IFNs) suppress megakaryocyte (MK) growth in myeloproliferative disorders (MPD). Recombinant alpha IFN (rIFN-alpha) inhibits MPD MKs, while rIFN-gamma shows limited effects, suggesting rIFN-alpha is more effective for thrombocytosis.
Area of Science:
- Hematology
- Immunology
- Cell Biology
Background:
- Interferons (IFNs) are known to inhibit hematopoietic progenitor cell proliferation.
- IFN treatments have reduced platelet counts in myeloproliferative disorders (MPD).
Purpose of the Study:
- To evaluate recombinant alpha and gamma IFN (rIFN-alpha, rIFN-gamma) effects on megakaryocyte (MK) growth.
- To investigate interactions between IFNs and growth factors (rIL-3, rGM-CSF) on MKs.
Main Methods:
- Liquid cultures of normal and MPD marrow cells were treated with rIFN-alpha and rIFN-gamma.
- Interactions with rIL-3, rGM-CSF, and PHA-LCM were examined.
- Dose-dependent inhibition and growth stimulation were assessed.
Main Results:
- rIFN-alpha caused dose-dependent inhibition of MK growth in both normal and MPD marrow.
- rIFN-gamma showed inhibition only in normal marrow at high concentrations and stimulated MK growth in some conditions.
- rIL-3 (30 U/ml) reversed rIFN-alpha's inhibitory effect, but rGM-CSF and lower rIL-3 did not.
Conclusions:
- MPD marrow MKs are not more sensitive to rIFN-alpha than normal MKs.
- rIFN-alpha is more effective than rIFN-gamma for controlling thrombocytosis in MPD.
- rIL-3 can overcome rIFN-alpha-induced MK growth inhibition.