Interleukin-11 stimulates the proliferation of human hematopoietic CD34+ and CD34+CD33-DR-cells and synergizes with stem cell factor, interleukin-3, and granulocyte-macrophage colony-stimulating factor

We have studied the effects of recombinant human interleukin-11 rhIL-11), alone and combined with stem cell factor (SCF or c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the proliferation of highly enriched human hematopoietic CD34⁺ and CD34⁺CD33^-DR^- progenitor cells. CD34⁺ cells were purified using the avidin-biotin immunoabsorption technique and CD33⁺DR⁺ cells were subsequently removed by immunomagnetic separation. The colony assays were performed in the presence and absence of exogenous serum. IL-11, as a single agent, induced the growth of a small number of colony-forming units-granulocyte/macrophage (CFU-GM) derived from purified CD34⁺ cells and failed to support the colony growth of CD34⁺CD33^-DR^- cells. The addition of erythropoietin (Epo) to LL-11 induced the growth of erythroid progenitors (BFU-E) derived from CD34⁺ cells but not from the same population depleted of CD33⁺DR⁺ cells. The combination of IL-11 1 with SCF, IL-3, or GM-CSF, in the presence of Epo, resulted in a synergistic or additive increase in the number of CFU cells (CFU-C) derived from both cell fractions. Moreover, the addition of SCF to IL-11 stimulated the development of macroscopic erythroid and multilineage colonies (cFu-GEMM) containing more than 10⁴ cells. A combination of three factors (IL-11, SCF, and IL-3) resulted in the increase of the number of colonies arising from CD34⁺ and CD34⁺CD33^-DR^- cells (but not of their size) compared to the cultures treated with IL-11 1 plus SCF or IL-11 1 plus IL-3. The pattern of proliferative response of primitive hematopoietic progenitor cells to IL-11 in serum-free conditions was very similar to the cultures grown in serum-containing medium. It is noteworthy that IL-11 and SCF yielded colony formation that was comparable to that observed in the presence of serum. The effects of IL-11 on CD34⁺CD33^-DR^- cells were also studied in a short-term suspension culture system, which was shown to be specific for evaluating the proliferation of pluripotent hematopoietic precursors (Delta assay). In this system, IL-11 had a minimal effect on its own, whereas IL-11 plus SCF acted synergistically and their proliferative activity was improved by the addition of GM-CSF. These experiments indicate that IL-11 may be considered a 'permissive' cytokine, capable of initiating the proliferation of very primitive human hematopoietic cells, which are then able to respond to late-acting CSFs. Also, IL-11 1 synergizes in vitro with SCF in expanding the pool of early hematopoietic progenitor cells.