MAST-CELL GROWTH-FACTOR (C-KIT LIGAND) IN COMBINATION WITH GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND INTERLEUKIN-3 - IN-VIVO HEMATOPOIETIC EFFECTS IN IRRADIATED MICE COMPARED TO IN-VITRO EFFECTS

In the presence of hemopoietic cytokines such as granulocyte-macrophag e colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast ce ll growth factor (MGF; also known as steel factor, stem cell factor, a nd c-kit ligand) has proven to be a potent hemopoietic regulator in vi tro. In these studies, we examined the in vivo effects of MGF in combi nation with GM-CSF or GM-CSF plus IL-3. Effects were based on the abil ity of these cytokines to stimulate recovery from radiation-induced he mopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75 -Gy dose of Co-60 radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 mu g/kg/day), rmGM-CS F (100 mu g/kg/day), rmIL-3 (100 mu g/kg/day), or combinations of thes e cytokines on days 1-17 postirradiation. Recoveries of bone marrow an d splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 eithe r produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results of in vitro studies evaluating the effects of these cytokines on inductio n of GM-CFC colony formation from bone marrow cells obtained from norm al or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or G M-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size . These studies demonstrate a dichotomy between MGF-induced effects in vivo and in vitro and emphasize that caution should be taken in attem pting to predict cytokine interactions in vivo in hemopoietically inju red animals based on in vitro cytokine effects.