Interleukin-11 (IL-11) and IL-9 counteract the inhibitory activity of transforming growth factor beta 3 (TGF-beta 3) on human primitive hematopoietic progenitor cells

Abstract

BACKGROUND. TGF-beta 3 has been proven to be a potent suppressor of human hematopoietic progenitor cells and its effects on hematopoiesis are only inhibitory. METHODS. In this paper we investigated the antiproliferative activity of TGF-beta 3 on highly purified bone marrow (BM) CD34+ cells and more immature CD34+/4-hydroperoxycyclophosphamide (4-HC) resistant cells. Primitive hematopoietic progenitors were stimulated by early acting stimulatory factors such as SCF, IL-11, IL-9 and the intermediate-late acting growth factors IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone and in combination. RESULTS. The addition of TGF-beta 3 to cultures of CD34+ cells containing IL-11, IL-9 or SCF alone resulted in 86% or more inhibition of total colony formation. Conversely, IL-3 and GM-CSF-stimulated colony growth was inhibited by 57% and 58%, respectively (p < 0.02). IL-11 and IL-9 acted synergistically or additively with IL-3 and GM-CSF on the clonogenic growth of BFU-E derived from CD34+ cells, in both the presence and absence of TGF-beta 3. Co-incubation of CD34+ cells with 2 synergistic factors (e.g. IL-11 and SCF or IL-9 and SCF), with or without TGF-beta 3, resulted in the enhancement of both CFU-GM and BFU-E growth. The percentage of CD34+ cells inhibited by TGF-beta 3 was significantly reduced when IL-11 or IL-9, but not SCF, was added to the other cytokines (e.g. IL-11 and IL-3-stimulated cultures were inhibited by 42%, compared to 57% and 90% for the CSF alone; p < 0.05). Similarly, the addition of IL-11 or IL-9 to SCF decreased the suppressive activity of TGF-beta 3 (e.g. IL-11 and SCF in combination were inhibited by 52.4%, compared to 90% or more when the same cytokines were used separately; p < 0.001). These effects were mainly observed on CD(34+)-derived BFU-E although IL-9 appeared to override TGF beta-3 on both CFU-GM and BFU-E. When tested on CD34+/4-HC resistant progenitors, IL-11, IL-9 and SCF increased the number of clonogenic cells responsive to IL-3 and GM-CSF. However, TGF-beta 3 demonstrated a greater inhibitory activity on earlier cells than on the more mature CD34+ cell fraction, and none of the study cytokines completely abrogated the activity of TGF-beta 3. CONCLUSIONS. These data confirm that TGF-beta 3 exerts its suppressive effect on hematopoietic progenitor cells according to the differentiation state of the target cells and the presence of other cytokines interacting with the cells. The permissive growth factors IL-11 and IL-9 seem to be able to partially counteract the negative regulation of TGF-beta 3.