Protein kinase C activators can interact synergistically with granulocyte colony-stimulating factor or interleukin-6 to stimulate colony formation from enriched granulocyte-macrophage colony-forming cells.
The effects of direct activators of protein kinase C (PKC) (the phorbol ester tetradecanoyl phorbol myristic acid [TPA] or bryostatin) on the ability of a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) to proliferate and develop in soft agar was assessed. In the absence of colony stimulating factors, the PKC activators did not stimulate colony formation. However, in the presence of optimal concentrations of granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6), TPA or bryostatin markedly elevated the number of colonies formed from the GM-CFC. In the absence of TPA, IL-6, and G-CSF, respectively, both stimulated the formation of about 3% of the colonies observed when IL-3 was present. When TPA plus G-CSF or IL-6 were added together, this figure increased to 48% and 54%, respectively. In both instances, the types of mature cells formed was altered from colonies of mature neutrophilic cells to a mixture consisting predominantly of macrophages with some neutrophils. Similar results were observed when bryostatin replaced TPA in these assays. When single cell colony-forming assays were performed, the same results were obtained. The presence of G-CSF, or IL-6, and the activator of PKC used (TPA or bryostatin) was required throughout the colony-forming assay for an optimal synergistic effect to be observed. These data indicate that agents that activate PKC can promote the proliferation and development of GM-CFC via a synergistic interaction with G-CSF or IL-6. Furthermore, there is an apparent role for PKC in development and possibly lineage commitment of GM-CFC.
Heyworth
C M
CM
Department of Experimental Haematology, Paterson Laboratories, Christie Hospital NHS Trust, Withington, Manchester, UK.
Dexter
T M
TM
Nicholls
S E
SE
Whetton
A D
AD
D000818:Animals; D015153:Blotting, Western; D054713:Bryostatins; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D054713:Bryostatins; D015850:Interleukin-6; D007783:Lactones; D018942:Macrolides; D016179:Granulocyte Colony-Stimulating Factor; C046785:bryostatin 1; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate