Abstract
Cytokines stimulate granulopoiesis through signaling via receptors whose expression is controlled by lineage-specific transcription factors. Previously, we demonstrated that granulocyte colony-stimulating factor (G-CSF) receptor mRNA was undetectable and granulocyte maturation blocked in CCAAT enhancer binding protein alpha (C/EBPalpha)-deficient mice. This phenotype is distinct from that of G-CSF receptor-/- mice, suggesting that other genes are likely to be adversely affected by loss of C/EBPalpha. Here we demonstrate loss of interleukin 6 (IL-6) receptor and IL-6-responsive colony-forming units (CFU-IL6) in C/EBPalpha-/- mice. The observed failure of granulopoiesis could be rescued by the addition of soluble IL-6 receptor and IL-6 or by retroviral transduction of G-CSF receptors, demonstrating that loss of both of these receptors contributes to the absolute block in granulocyte maturation observed in C/EBPalpha-deficient hematopoietic cells. The results of these and other studies suggest that additional C/EBPalpha target genes, possibly other cytokine receptors, are also important for the block in granulocyte differentiation observed in vivo in C/EBPalpha-deficient mice.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
CCAAT-Enhancer-Binding Proteins
-
Cell Differentiation / genetics
-
Colony-Forming Units Assay
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
DNA-Binding Proteins / physiology*
-
Drug Synergism
-
Enhancer Elements, Genetic
-
Fetus
-
Granulocytes / physiology*
-
Hematopoiesis* / drug effects
-
Hematopoiesis* / genetics
-
Hematopoietic Stem Cells / drug effects
-
Hematopoietic Stem Cells / metabolism
-
Humans
-
Interleukin-6 / pharmacology
-
Liver / cytology
-
Liver / drug effects
-
Liver / physiology
-
Mice
-
Mice, Knockout
-
Mutation
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Nuclear Proteins / physiology*
-
RNA, Messenger / antagonists & inhibitors
-
RNA, Messenger / biosynthesis
-
Receptors, Granulocyte Colony-Stimulating Factor / antagonists & inhibitors
-
Receptors, Granulocyte Colony-Stimulating Factor / biosynthesis*
-
Receptors, Granulocyte Colony-Stimulating Factor / deficiency
-
Receptors, Granulocyte Colony-Stimulating Factor / genetics
-
Receptors, Interleukin-6 / antagonists & inhibitors
-
Receptors, Interleukin-6 / biosynthesis*
-
Receptors, Interleukin-6 / deficiency
-
Receptors, Interleukin-6 / genetics
-
Solubility
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Up-Regulation / genetics
-
Up-Regulation / physiology*
Substances
-
CCAAT-Enhancer-Binding Proteins
-
DNA-Binding Proteins
-
Interleukin-6
-
Nuclear Proteins
-
RNA, Messenger
-
Receptors, Granulocyte Colony-Stimulating Factor
-
Receptors, Interleukin-6
-
Transcription Factors