Interactions among colony-stimulating factors, IL-1 beta, IL-6, and kit-ligand in the regulation of primitive murine hematopoietic cells.
We have investigated the regulation of primitive murine hematopoietic progenitors by the cytokines interleukin 1 (IL-1), interleukin 6 (IL-6), and kit-ligand (KL). Individually these cytokines have a limited ability to stimulate the growth of high proliferative potential colony-forming cells (HPP-CFC) from 5-fluorouracil (5-FU)-purged bone marrow, but in combination these cytokines demonstrate synergism in promoting the growth of HPP-CFC. Furthermore, IL-1, IL-6, and KL, alone or in combination, synergized with the colony-stimulating factors (CSFs) granulocyte CSF (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin 3 (IL-3) in clonal and liquid cultures of 5-FU-purged bone marrow. The pattern of HPP-CFC growth that was observed with 40 different cytokine combinations demonstrated the unique roles of IL-1, IL-6, and KL in the regulation of HPP-CFC proliferation. Short-term liquid cultures (delta-cultures), with secondary recloning, of 5-FU-purged bone marrow were stimulated to greatly expand the numbers of progenitor cells generated in response to cytokine stimulation. The greatest expansion, over 1800-fold, of the more mature progenitor compartments took place in delta-cultures stimulated with IL-1, IL-6, and KL plus IL-3. However, the combination of IL-1 and IL-6 plus KL was optimal in expanding HPP-CFC, increasing their numbers by 700-fold. The ability to expand early progenitor cells in delta-cultures was further demonstrated by the greater than 100-fold expansions of day-12 spleen colony-forming units (CFU-S) by the synergistic interactions of IL-1 with IL-3 or KL.
Muench
M O
MO
James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, New York.
Schneider
J G
JG
Moore
M A
MA
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit
D016207:Cytokines; D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil