Ectopic expression of interferon regulatory factor-1 potentiates granulocytic differentiation.
Numerous transcription factors allow haematopoietic cells to respond to lineage- and stage-specific cytokines and to act as their effectors. It is increasingly evident that the interferon regulatory factor-1 (IRF-1) transcription factor can selectively regulate different sets of genes depending on the cell type and/or the nature of cellular stimuli, evoking distinct responses in each. In the present study, we investigated mechanisms underlying the differentiation-inducing properties of granulocytic colony-stimulating factor (G-CSF) and whether IRF transcription factors are functionally relevant in myeloid differentiation. Both normal human progenitors and murine 32Dcl3 myeloblasts induced to differentiate along the granulocytic pathway showed an up-regulation of IRF-1 expression. Ectopic expression of IRF-1 did not abrogate the growth factor requirement of 32Dcl3 cells, although a small percentage of cells that survived cytokine deprivation differentiated fully to neutrophils. Moreover, in the presence of G-CSF, granulocytic differentiation of IRF-1-expressing cells was accelerated, as assessed by morphology and expression of specific differentiation markers. Down-modulation of c-Myb protein and direct stimulation of lysozyme promoter activity by IRF-1 were also observed. Conversely, constitutive expression of IRF-2, a repressor of IRF-1 transcriptional activity, completely abrogated the G-CSF-induced neutrophilic maturation. We conclude that IRF-1 exerts a pivotal role in granulocytic differentiation and that its induction by G-CSF represents a limiting step in the early events of differentiation.
Coccia
E M
EM
Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy.
Stellacci
E
E
Valtieri
M
M
Masella
B
B
Feccia
T
T
Marziali
G
G
Hiscott
J
J
Testa
U
U
Peschle
C
C
Battistini
A
A
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006098:Granulocytes / Q000166:cytology* / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology; D006133:Growth Substances / Q000172:deficiency; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D000099232:Proto-Oncogene Protein Spi-1
D015415:Biomarkers; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D016179:Granulocyte Colony-Stimulating Factor; D006131:Growth Inhibitors; D006133:Growth Substances; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma; D009113:Muramidase; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C494257:IRF1 protein, human; C494229:IRF2 protein, human; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse