Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors

Objective. Erythropoiesis is positively regulated by stem cell factor, inte rleukin 3, and erythropoietin, which synergize to allow the production of h emoglobinized red blood cells from erythroid progenitors. In contrast, inte rferon gamma, tumor necrosis factor alpha, and transforming growth factor b eta(1), (TGF-beta(1)) are powerful inhibitors of erythropoiesis. Interferon gamma and alpha act principally by inducing apoptosis, The aim of this stu dy was to elucidate the mechanisms by which TGF-beta(1) inhibits erythropoi esis. Materials and methods. We used an in vitro serum-free system of human red b lood cell production, From a virtually pure population of CD36(+) erythroid progenitors, stem cell factor, interleukin 3, and erythropoietin allowed m assive proliferation (x300) and promoted terminal red blood cell differenti ation. Results. We show here that TGF-beta(1) (2 ng/mL) inhibited the growth of CD 36(+) cells by 15-fold. TGF-beta(1) markedly accelerated and increased eryt hroid differentiation as assessed by hemoglobin and glycophorin expression, Furthermore, May-Grunwald-Giemsa staining and ultrastructural analysis rev ealed that TGF-beta(1) induced full differentiation toward normal enucleate d red cells even in the absence of macrophages, This acceleration of erythr oid differentiation did not modify the pattern of hemoglobin chains express ion from adult or fetal erythroid progenitors. Analysis of apoptosis, cell cycle and Ki-67 expression showed that TGF-beta(1) inhibited cell prolifera tion by decreasing the cycle of immature erythroid cells and accelerating m aturation toward orthochromatic normoblasts that are not in cycle. Conclusion. We showed that TGF-beta(1) is a paradoxical inhibitor of erythr opoiesis that acts by blocking proliferation and accelerating differentiati on of erythroid progenitors, (C) 2000 International Society fur Experimenta l Hematology. Published by Elsevier Science Inc.