Effect of adenine nucleotides on granulopoiesis and lithium-induced granulocytosis in long-term bone marrow cultures.
Studies were undertaken to evaluate the role of adenine nucleotides in regulating hematopoiesis using a long-term liquid culture system. In contrast to early investigations using clonogenic stem cell assays, where inhibitory effects were observed, adenosine and adenosine-5'-monophosphate (AMP) were found to stimulate myelopoiesis whereas the dibutyryl derivative of cyclic adenosine-3',5'-monophosphate (dcAMP) had either a modest inhibitory effect or no effect on long-term hematopoiesis. Dose effects for AMP enhancement of hematopoiesis were relatively narrow. When cultures were exposed to a broad range of concentrations (10 mM-10 nM), stimulation was only seen at a molar concentration of 1 X 10(-4) M. Stem cell assays revealed stimulation of multipotent stem cells (CFU-S), as well as committed progenitor cells (CFU-C). Lithium chloride has been shown to cause granulocytosis both in vivo and in vitro. Reductions in intracellular cAMP levels resulting from adenylate cyclase inhibition is a proposed mechanism for this stimulatory effect. However, lithium-induced granulocytosis in long-term cultures could not be blocked by the addition of dcAMP. Measurement of nucleotide levels on spent medium revealed rapid utilization and/or degradation of these reagents. This suggests that failure to abrogate the lithium effect with dcAMP may have been related to the inability to maintain constant intracellular concentrations. The varied observations regarding adenine nucleotide effects on hematopoiesis, as well as the reproducible stimulation by lithium, may be explained by our current appreciation of the complex adenylate cyclase system, which contains both inhibitory and stimulatory subunits for nucleotides and monovalent cations.
D000241:Adenosine / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D003994:Bucladesine / Q000494:pharmacology*; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology*; D005260:Female; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology*; D018021:Lithium Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR
D002712:Chlorides; D000249:Adenosine Monophosphate; D003994:Bucladesine; D008094:Lithium; D018021:Lithium Chloride; D000241:Adenosine