Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes.
Human interferon (IFN)-alpha is the standard therapy for chronic hepatitis C to prevent its progression to liver cirrhosis and hepatocellular carcinoma. Thrombocytopenia is one of the major adverse effects of IFN-alpha and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN-alpha inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-alpha did not inhibit colony formation of megakaryocytes from human CD34(+) hematopoietic stem cells. IFN-alpha did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN-alpha suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45(NF-E2), MafG. IFN-alpha also significantly reduced the number of human platelets but not megakaryocytes, and did not inhibit endomitosis of human megakaryocytes in immunodeficient NOD/Shi-scid/IL-2R gamma(null) (NOG) mice transplanted with human CD34(+) cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-alpha-induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN-alpha inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-alpha. These results defined the pathogenesis of IFN-alpha-induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Akiko
A
Yamane
Takanori
T
Nakamura
Hidenori
H
Suzuki
Mamoru
M
Ito
Yasuyuki
Y
Ohnishi
Yasuo
Y
Ikeda
Yoshitaka
Y
Miyakawa
D001854:Bone Marrow Cells; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects*; D008533:Megakaryocytes / Q000166:cytology* / Q000648:ultrastructure; D008938:Mitosis; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000139:chemically induced*; D034061:Thrombopoiesis / Q000187:drug effects*; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014157:Transcription Factors