IFN consensus sequence binding protein/IFN regulatory factor-8 guides bone marrow progenitor cells toward the macrophage lineage.
IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in myeloid cell development, lineage marker-negative (Lin(-)) bone marrow progenitor cells were purified from ICSBP(+/+) and ICSBP(-/-) mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin(-) progenitor cells, and its levels were markedly increased by IFN-gamma. The colony-forming potential of ICSBP(-/-) progenitor cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-gamma inhibited colony formation, while promoting macrophage maturation in ICSBP(+/+) cells. In contrast, the effects of IFN-gamma were completely absent in ICSBP(-/-) progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in -/- progenitor cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in myeloid cell development by controlling lineage selection and is indispensable for IFN-gamma-dependent modulation of progenitor cell maturation.
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Hideki
H
Tsujimura
Tokiko
T
Nagamura-Inoue
Tomohiko
T
Tamura
Keiko
K
Ozato
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8
D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D016173:Macrophage Colony-Stimulating Factor; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8