The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/1173/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1173-1184


Articles

Upregulation of Interleukin 6 and Granulocyte Colony-Stimulating Factor Receptors by Transcription Factor CCAAT Enhancer Binding Protein {alpha} (C/EBP{alpha}) Is Critical for Granulopoiesis

Pu Zhang*, Atsushi Iwama*, Milton W. Datta*, Gretchen J. Darlington{ddagger}, Daniel C. Link§, and Daniel G. Tenen*

From the * Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; the {ddagger} Department of Pathology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030; and the § Division of Bone Marrow Transplantation and Stem Cell Biology, Department of Medicine, Washington University Medical School, St. Louis, Missouri 63110-1093

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/EBP{alpha})-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/EBP{alpha}. Here we demonstrate loss of interleukin 6 (IL-6) receptor and IL-6–responsive colony-forming units (CFU-IL6) in C/EBP{alpha}–/– 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/EBP{alpha}-deficient hematopoietic cells. The results of these and other studies suggest that additional C/EBP{alpha} target genes, possibly other cytokine receptors, are also important for the block in granulocyte differentiation observed in vivo in C/EBP{alpha}-deficient mice.

Key Words: CCAAT enhancer binding protein • knockout mice • colony-forming unit • hematopoiesis • myelopoiesis


Address correspondence to Daniel G. Tenen, Harvard Institutes of Medicine, Rm. 954, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: 617-667-5561; Fax: 617-667-3299; E-mail: dtenen{at}bidmc.harvard.edu

Abbreviations used: C/EBP, CCAAT enhancer binding protein; CFU-GM, GM-CSF–responsive CFU; CFU-IL3 and -IL6, IL-3 and IL-6–responsive CFU, respectively; RT, reverse transcription; SCF, stem cell factor.


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