Submitted December 3, 2007
Accepted April 6, 2008
Interferon-
2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes
Akiko Yamane, Takanori Nakamura, Hidenori Suzuki, Mamoru Ito, Yasuyuki Ohnishi, Yasuo Ikeda, and Yoshitaka Miyakawa*
Division of Hematology, Keio University School of Medicine, Tokyo, Japan
Biological Reseach Laboratories, Nissan Chemical Industries, Saitama, Japan
Medical Research and Development Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Central Institute for Experimental Animals, Kanagawa, Japan
* Corresponding author; email: yoshi{at}sc.itc.keio.ac.jp.
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-positive 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 and 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-positive 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, though 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.
