Kinetic analysis of megakaryopoiesis induced by recombinant human interleukin 11 in myelosuppressed mice.
Recombinant human interleukin 11 (rhIL-11) has previously been shown to ameliorate thrombocytopenia in several animal models. To elucidate the mechanisms involved in rhIL-11-induced hematopoiesis, a kinetic analysis of megakaryopoiesis was performed in mitomycin C (MMC)-induced myelosuppressive mice. Mice intravenously injected with MMC (2 mg/kg) for two consecutive days from day -1 developed severe thrombocytopenia with a nadir of platelet counts at 24x10(4)/microl on day 12 and neutropenia. Treatment with rhIL-11 (500 microg/kg/day) from day 1 to 21 significantly ameliorated the degree and duration of thrombocytopenia and enhanced the platelet recovery, and also enhanced the recovery from neutropenia. In MMC-treated mice, the decreases in bone marrow megakaryocyte progenitors and megakaryocyte counts preceded the decrease in platelet counts by MMC treatment. RhIL-11 induced an increase in the number of megakaryocyte progenitors from day 4 to 14, followed by an increase in the megakaryocytes by day 20. There was a ploidy shift in megakaryocytes towards lower ploidy cells by day 9 in myelosuppressed mice. RhIL-11 caused a shift towards a higher ploidy with 32 and 64N on day 4, and 32N on day 14. These results suggest that rhIL-11 ameliorates the thrombocytopenia via the stimulation of both the maturation and commitment followed by the proliferation of megakaryocytic cells.
Saitoh
M
M
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan. saitoh_m@yamanouchi.co.jp
Taguchi
K
K
Momose
K
K
Suga
K
K
Ogawa
Y
Y
Yasuda
S
S
Miyata
K
K
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D005260:Female; D005269:Femur / Q000166:cytology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017370:Interleukin-11 / Q000494:pharmacology*; D007700:Kinetics; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011003:Ploidies; D011994:Recombinant Proteins / Q000494:pharmacology*; D013234:Stem Cells; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors
D000477:Alkylating Agents; D007166:Immunosuppressive Agents; D017370:Interleukin-11; D019384:Nucleic Acid Synthesis Inhibitors; D011994:Recombinant Proteins; D016685:Mitomycin