IL-3 does not contribute to platelet production in c-Mpl-deficient mice

Thrombopoietin is a lineage-dominant cytokine involved primarily in the control of platelet production. The physiological importance of thrombopoietin (TPO) in the regulation of megakaryocyte and platelet production was demonstrated by the production of mice deficient in TPO or its receptor, c-Mpl. Even though these mice are profoundly thrombocytopenic they maintain a basal level of approximately 10% of the normal count of fully functional platelets. These platelets prevent any abnormal bleeding episodes and highlight the potential importance of other factors in the control of platelet production. Among the factors with in vitro megakaryocytopoietic activity, the most potent is undoubtedly interleukin 3 (IL-3). To analyze the contribution of IL-3 to platelet formation in the absence of TPO, we have generated mice deficient in both c-Mpl and IL-3Ralpha by taking advantage of a natural mutation present in this gene in the A/J mouse. Surprisingly, these double knockout mice did not show any further reduction in their platelet or megakaryocyte counts when compared with c-Mpl-deficient mice. Similarly, progenitors from other lineages that are also reduced in c-Mpl-deficient mice are not further affected by the absence of a functional IL-3Ralpha gene. These results demonstrate that IL-3 alone is not responsible for the production of a basal level of normal platelets in the absence of thrombopoietin signaling.