Mast cell growth factor (C-kit ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3: in vivo hemopoietic effects in irradiated mice compared to in vitro effects.
In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulator in vitro. In these studies, we examined the in vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 micrograms/kg/day), rmGM-CSF (100 micrograms/kg/day), rmIL-3 (100 micrograms/kg/day), or combinations of these cytokines on days 1-17 postirradiation. Recoveries of bone marrow and 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 either 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 induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-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 attempting to predict cytokine interactions in vivo in hemopoietically injured animals based on in vitro cytokine effects.
Patchen
M L
ML
Department of Experimental Hematology, Armed Forces Radiobiology, Research Institute Bethesda, MD.
Fischer
R
R
MacVittie
T J
TJ
Seiler
F R
FR
Williams
D E
DE
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D001854:Bone Marrow Cells; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D007377:Interleukin-3 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D019089:Stem Cell Factor; D014916:Whole-Body Irradiation
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor