Interferon-gamma antagonizes interleukin-6-induced expression of interleukin-4 receptors in murine myeloid cells by a transcriptional mechanism.
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-gamma (IFN-gamma), 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-gamma downregulates the IL-6-induced expression of IL-4R whereas it has no such effect on the high-affinity receptors for monomeric IgG2a (Fc gamma RI). As demonstrated by Scatchard analysis, the number of IL-4R decreases by more than 50% after IFN-gamma treatment whereas the receptor affinity remains unchanged. Northern analysis shows that this decrease is paralleled by a decrease in IL-4R mRNA but not Fc gamma RI or lysozyme mRNA. Nuclear run-on analysis shows that IFN-gamma 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-gamma as well. These data explain how IL-4R can be modulated by IFN-gamma in myeloid cells and are consistent with the myelosuppressive capacity of IFN-gamma.
Ruhl
S
S
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
Feldman
G M
GM
Akahane
K
K
Pluznik
D H
DH
D000818:Animals; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009113:Muramidase / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017452:Receptors, IgG / Q000032:analysis; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D007371:Interferon-gamma; D009113:Muramidase; D012333:RNA, Messenger; D017452:Receptors, IgG; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D000093242:Interleukin-6 Inhibitors