The residual megakaryocyte and platelet production in c-mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor.
Mice lacking thrombopoietin (TPO) or its receptor c-Mpl are severely thrombocytopenic, consistent with a dominant physiological role for this cytokine in megakaryocytopoiesis. However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis. To investigate the roles of cytokines that act through the gp130 signaling chain in the residual platelet production of mpl (-/-) mice, mpl (-/-)IL-6(-/-), mpl(-/-)LIF(-/-), and mpl(-/-)IL-11Ralpha(-/-) double-mutant mice were generated. In each of these compound mutants, the number of circulating platelets was no lower than that observed in mice lacking only the c-mpl gene. Moreover, the deficits in the numbers of megakaryocytes and megakaryocyte progenitor cells in the bone marrow and spleen were no further exacerbated in mpl(-/-)IL-6(-/-), mpl(-/-)LIF(-/-), or mpl(-/-)IL-11Ralpha(-/-) double-mutant mice compared with those in Mpl-deficient animals. In single IL-6(-/-), LIF(-/-), and IL-11Ralpha(-/-) mutant mice, platelet production was normal. These data establish that, as single regulators, IL-6, IL-11, and LIF have no essential role in normal steady-state megakaryocytopoiesis, and are not required for the residual megakaryocyte and platelet production seen in the c-mpl(-/-) mouse. (Blood. 2000;95:528-534)
Gainsford
T
T
The Walter and Eliza Hall Institute for Medical Research, the Cooperative Research Centre for Cellular Growth Factors and the Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Victoria, Australia.
Nandurkar
H
H
Metcalf
D
D
Robb
L
L
Begley
C G
CG
Alexander
W S
WS
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology*; D005838:Genotype; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D017370:Interleukin-11 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013154:Spleen / Q000166:cytology*; D013926:Thrombopoietin / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D006131:Growth Inhibitors; D017370:Interleukin-11; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin