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Blood, 1 August 2008, Vol. 112, No. 3, pp. 542-550.
Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2007-12-125906.
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HEMATOPOIESIS AND STEM CELLS
Interferon- 2b–induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes
Akiko Yamane1,*,
Takanori Nakamura1,2,*,
Hidenori Suzuki3,
Mamoru Ito4,
Yasuyuki Ohnishi4,
Yasuo Ikeda1, and
Yoshitaka Miyakawa1
1 Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo;
2 Biological Research Laboratories, Nissan Chemical Industries, Saitama;
3 Medical Research and Development Center, Tokyo Metropolitan Institute of Medical Science, Tokyo; and
4 Central Institute for Experimental Animals, Kanagawa, Japan
Human interferon (IFN)– 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- and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN- inhibits human megakaryopoiesis. In this study, we demonstrated that IFN- did not inhibit colony formation of megakaryocytes from human CD34+ hematopoietic stem cells. IFN- did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN- suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45NF-E2, MafG. IFN- 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 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-–induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN- inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-. These results defined the pathogenesis of IFN-–induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.
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