Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Animals
-
Biomarkers / analysis
-
Cell Differentiation / genetics
-
Cell Line
-
Culture Media, Conditioned
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / biosynthesis*
-
DNA-Binding Proteins / genetics*
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / physiology
-
Down-Regulation / genetics
-
Enzyme Activation / genetics
-
Gene Expression Regulation
-
Genetic Vectors
-
Granulocyte Colony-Stimulating Factor / antagonists & inhibitors
-
Granulocyte Colony-Stimulating Factor / deficiency
-
Granulocyte Colony-Stimulating Factor / genetics
-
Granulocyte Colony-Stimulating Factor / physiology
-
Granulocytes / cytology*
-
Granulocytes / physiology
-
Growth Inhibitors / physiology
-
Growth Substances / deficiency
-
Hematopoiesis / genetics
-
Humans
-
Interferon Regulatory Factor-1
-
Interferon Regulatory Factor-2
-
Interferon-gamma / physiology*
-
Mice
-
Muramidase / genetics
-
Muramidase / metabolism
-
Phosphoproteins / biosynthesis*
-
Phosphoproteins / genetics*
-
Phosphoproteins / metabolism
-
Phosphoproteins / physiology
-
Protein Binding / genetics
-
Proto-Oncogene Proteins / biosynthesis
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins c-myb / antagonists & inhibitors
-
Proto-Oncogene Proteins c-myb / biosynthesis
-
Proto-Oncogene Proteins c-myb / genetics
-
Repressor Proteins*
-
Trans-Activators / biosynthesis
-
Trans-Activators / genetics
-
Transcription Factors / biosynthesis*
-
Transcription Factors / genetics*
-
Transcription Factors / physiology
-
Transfection
Substances
-
Biomarkers
-
Culture Media, Conditioned
-
DNA-Binding Proteins
-
Growth Inhibitors
-
Growth Substances
-
IRF1 protein, human
-
IRF2 protein, human
-
Interferon Regulatory Factor-1
-
Interferon Regulatory Factor-2
-
Irf1 protein, mouse
-
Irf2 protein, mouse
-
Phosphoproteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-myb
-
Repressor Proteins
-
Trans-Activators
-
Transcription Factors
-
proto-oncogene protein Spi-1
-
Granulocyte Colony-Stimulating Factor
-
Interferon-gamma
-
Muramidase