Enhanced Platelet Recovery in Myelosuppressed Mice Treated with Interleukin-1 and Macrophage Colony-Stimulating Factor: Potential Interactions with Cytokines Having Megakaryocyte Colony-Stimulating Activity

Studies were carried out to determine whether the combination of IL-1 + M-CSF, similar to the effect of these cytokines on neutropenia, was able to reduce the duration of thrombocytopenia in the 5-fluorouracil (5-FU)myelosuppressed mouse. In addition, comparisons were made between the in vivo effects of IL-1 + M-CSF and other "thrombopoietic" cytokines (e.g., IL-3, IL-6, and GM-CSF) that demonstrate some form of megakaryocytopoietic activity in vitro. Of the five cytokines studied, only IL-1 and IL-6, by themselves, were able to effect thrombopoietic recovery in the myelosuppressed mouse. IL-1, either when acting alone or interacting synergistically with M-CSF, was able to reduce significantly the period of thrombocytopenia, but the effects of IL-6 were restricted to enhancing platelet production during the period of rebound thrombocytopenia without altering the kinetics of thrombopoietic recovery. Moreover, none of the cytokine combinations studied were found to interact to reduce further the duration of thrombocytopenia beyond that observed with IL-1 + M-CSF. Nonetheless, IL-3, IL-6, and, to a lesser extent, GM-CSF were each able to interact with IL-1 + M-CSF to extend further the period of enhanced platelet production in the animal. However, scheduling studies suggested that these thrombopoietic cytokines interacted in sequence, rather than in concert, with IL-1 + M-CSF to enhance platelet production during thrombopoietic recovery. Furthermore, the data presented are consistent with the hypothesis that IL-1 + M-CSF initially acts on a multilineage, 5-FU-resistant target cell and that IL-6 (and possibly IL-3 and GM-CSF) serves as a secondary cytokine further to enhance platelet production during rebound thrombopoiesis in the 5-FU-treated mouse.