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.
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan. saitoh_m@yamanouchi.co.jp
M
M
Saitoh
K
K
Taguchi
K
K
Momose
K
K
Suga
Y
Y
Ogawa
S
S
Yasuda
K
K
Miyata
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