Growth factors controlling interleukin-4 action on hematopoietic progenitors

Abstract

We investigated the effect of interleukin-4 (IL-4) on human hematopoietic progenitors using low-density bone marrow cells from 29 hematologically normal donors. We found that IL-4 could either inhibit or stimulate cell growth, depending upon the other constituents of the culture medium. At concentrations ranging from 0.1 to 10.0 micrograms/ml, it significantly inhibited colony-forming units granulocyte-macrophage (CFU-GM) in the presence of either fetal calf serum alone, erythropoietin, leukocyte-conditioned medium prepared with phytohemagglutinin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), or stem cell factor (SCF), in a dose-dependent fashion. In contrast, IL-4 stimulated CFU-GM colony multiplication in the presence of granulocyte colony-stimulating factor (G-CSF). Similar but less significant inhibitory effects were exerted by IL-4 on burst-forming units-erythroid (BFU-E). The growth-suppressive effect of IL-4 was partially reversed by IL-1 beta, and to a lesser extent by IL-6. When tested by enzyme-linked immunosorbent assay (ELISA), IL-4 suppressed cellular IL-1 beta production, and, similar to IL-4, anti-IL-1 beta-neutralizing antibodies inhibited CFU-GM colony growth, suggesting that the inhibition of endogenous IL-1 beta is a factor in regulating the IL-4 effect. Furthermore, in the absence of exogenous growth factors, IL-4 inhibited CFU-GM colony growth when anti-G-CSF neutralizing antibodies were also present. Therefore, we tested the effect of IL-4 on G-CSF receptors and found that 6- or 24-h incubation of low-density marrow cells with 1.0 microgram/ml IL-4 resulted in up-regulation of G-CSF receptors. Taken together, these results suggest that IL-4 possesses a dual modulatory role in the hematopoietic system via interaction with various cytokines.