Interferon-gamma increases the expression of the gene encoding the beta subunit of the granulocyte-macrophage colony-stimulating factor receptor.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) activates a broad range of myeloid cells through binding to high-affinity receptors (GM-CSF-R) consisting of at least two distinct subunits, GM-CSF-R alpha and GM-CSF-R beta. The genes of these GM-CSF-R subunits have been identified recently, but little is known about the regulation of their expression. In this study, we investigated the expression of the GM-CSF-R subunit genes in normal human monocytes. Out of a panel of various cytokines and factors tested, only interferon-gamma (IFN-gamma) affected the expression of one of the GM-CSF-R subunit genes by increasing the GM-CSF-R beta mRNA expression threefold to sixfold with no effect on GM-CSF-R alpha. Maximal effects occurred 2 to 4 hours after stimulation with 500 to 5,000 U/mL IFN-gamma. Nuclear run-on assays and mRNA half-life studies showed that IFN-gamma modestly enhanced the transcription of the GM-CSF-R beta gene and stabilized the GM-CSF-R beta mRNA, with the latter mechanism predominant. Pretreatment of the monocytes with cycloheximide did not abrogate the increase of GM-CSF-R beta mRNA expression induced by IFN-gamma, indicating that de novo protein synthesis was not required for this activity. When monocytes were exposed to IFN-gamma for 6 to 24 hours, the number of GM-CSF-R per cell was increased 79% as compared with controls, whereas the receptor affinity remained unchanged. These data indicate that the GM-CSF-R expression in monocytes may be upregulated by IFN-gamma via an increased expression of the beta subunit gene, involving both transcriptional and post-transcriptional mechanisms.
Hallek
M
M
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115.
Lepisto
E M
EM
Slattery
K E
KE
Griffin
J D
JD
Ernst
T J
TJ
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D046911:Macromolecular Substances; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D046911:Macromolecular Substances; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide