Thymosin beta 4 synergizes with human granulocyte-macrophage colony-stimulating factor in maintaining bone marrow proliferation.
Recent evidence supports a role for thymosin beta 4 (T beta 4) in the inhibition of murine hematopoietic stem cell proliferation. This supposition results from studies in which the N-terminal tetrapeptide derived from native T beta 4 was administered to mice and appeared to prevent CFU-S recruitment into DNA synthesis. The importance of this observation was the concomitant ability of the tetrapeptide to prevent cytosine arabinoside (ara-C) toxicity in mice given LD50 doses of this drug. In the present study, we have extended these observations by demonstrating that whole synthetic T beta 4 is more effective than the N-terminal tetrapeptide in protecting mice from the toxicity of ara-C. This observation supports the hypothesis that T beta 4 is the biologically important parent molecule for this activity. To determine if inhibition of cell cycle progression also occurs in committed human bone marrow progenitors treated with T beta 4, we have investigated the effects of synthetic T beta 4 on proliferating and unstimulated enriched human bone marrow. In short-term liquid cultures studied sequentially over 1-7 days, T beta 4 failed to inhibit cell proliferation, but maintained the proliferative effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on days following maximum stimulation (days 5-7). No effect was noted before the fifth day in culture, nor did T beta 4 exert any demonstrable effect in the absence of added GM-CSF. Any observable effect of T beta 4 required that it be present in the cultures on or before day 3 of GM-CSF stimulation. These results suggest that an additional effect of T beta 4 is the stimulation of a subpopulation of committed human bone marrow precursor cells to become more sensitive to the growth-promoting activity of GM-CSF, thereby enhancing myelopoiesis. It is of interest that the N-terminal peptide of T beta 4 is a shared sequence with tumor necrosis factor alpha, which is also known to have a similar stimulatory capacity. We, therefore, postulate that the growth enhancement noted in short-term cultures is mediated by the region containing these shared sequences.
Moscinski
L C
LC
Department of Pathology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa 33682.
Naylor
P H
PH
Oliver
J
J
Goldstein
A L
AL
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000633:toxicity; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D013947:Thymosin / Q000494:pharmacology*; D000099201:Thymosin beta(4)
D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D013947:Thymosin; D000099201:Thymosin beta(4)