J. Exp. Med., Volume 188, Number 6, September 21, 1998 1173-1184

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

By Pu Zhang,^* Atsushi Iwama,^* Milton W. Datta,^* Gretchen J. Darlington, 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  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  (C/EBP)-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. Here we demonstrate loss of interleukin 6 (IL-6) receptor and IL-6-responsive colony-forming units (CFU-IL6) in C/EBP^/ 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-deficient hematopoietic cells. The results of these and other studies suggest that additional C/EBP target genes, possibly other cytokine receptors, are also important for the block in granulocyte differentiation observed in vivo in C/EBP-deficient mice.

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