Interferon-γ antagonizes interleukin-6-induced expression of interleukin-4 receptors in murine myeloid cells by a transcriptional mechanism

Abstract

The murine myeloid leukemia cell line M1 induced by interleukin-6 (IL-6) is a model system to study the differentiation of blast cells to mature macrophages. We have recently shown that IL-6 induces the expression of the IL-4 receptor (IL-4R) in these cells. In the present study we investigate the mechanism of action of interferon-γ (IFN-γ), an antagonist of IL-4 in numerous cells and a cofactor in both induction and suppression of myelopoiesis, on the expression of IL-4R. Flow cytometry shows that IFN-γ downregulates the IL-6-induced expression of IL-4R whereas it has no such effect on the high-affinity receptors for monomeric IgG2a (FcγRI). As demonstrated by Scatchard analysis, the number of IL-4R decreases by more than 50% after IFN-γ treatment whereas the receptor affinity remains unchanged. Northern analysis shows that this decrease is paralleled by a decrease in IL-4R mRNA but not FcγRI or lysozyme mRNA. Nuclear run-on analysis shows that IFN-γ suppresses the IL-6-induced transcription of the IL-4R gene, whereas actinomycin-D chase experiments showed no change of IL-4R mRNA stability. Furthermore, the production of soluble IL-4R protein is suppressed by IFN-7 as well. These data explain how IL-4R can be modulated by IFN-γ in myeloid cells and are consistent with the myelosuppressive capacity of IFN-γ.