Direct effects of cyclosporin A on proliferation of hematopoietic stem and progenitor cells.
Cyclosporin A (Cy A) has been reported to both stimulate and inhibit bone marrow colony assays in a dose-dependent manner. The observation that anti-gamma-IFN antibodies stimulate hematopoiesis to the same degree as Cy A has led several groups to propose that the stimulatory effects of Cy A are due to inhibition of gamma-IFN production by T cells. In this study we observed that cultures of highly enriched hematopoietic stem/progenitor cells (HSPC), devoid of CD3/5/8+ T cells, also exhibit enhanced cloning efficiency when cultured in the presence of Cy A. Normal bone marrow cells or Thy-1.1lowSca-1+Lin(neg) HSPC were incubated in methylcellulose cultures and stimulated with various combinations of steel factor (SF), interleukin (IL)-3, IL-6, granulocyte colony stimulating factor (G-CSF), and erythropoietin (EPO) in the presence of increasing concentrations of Cy A. HSPC cultures with SF, IL-3, and IL-6 stimulation and low Cy A concentrations had from 24% to 78% higher cloning efficiencies than did parallel cultures without Cy A, and did not fall below control levels until the Cy A concentration was increased to more than 1.25 microg/ml. The addition of EPO and G-CSF abrogated the Cy A stimulation observed with SF, IL-3, and IL-6. These results were reflected in whole bone marrow, but with a higher range of variability. Cultures in which FK-506 replaced Cy A showed no consistent stimulation or inhibition of colony formation. These studies show that Cy A can stimulate hematopoietic stem cell growth independent of mediation by T cells. Consequently, these results argue for a direct positive effect of Cy A on the signal transduction pathways in HSPC.
Perry
S S
SS
Department of Oncological Sciences, University of Utah Medical Center, Salt Lake City 84132, USA.
Kim
M
M
Spangrude
G J
GJ
D000818:Animals; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D004921:Erythropoietin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D019089:Stem Cell Factor / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007377:Interleukin-3; D015850:Interleukin-6; D019089:Stem Cell Factor; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D016572:Cyclosporine; D016559:Tacrolimus