UP-REGULATION OF INTERLEUKIN-6 AND GRANULOCYTE-COLONY-STIMULATING FACTOR RECEPTORS BY TRANSCRIPTION FACTOR CCAAT ENHANCER-BINDING PROTEIN-ALPHA (C EBP-ALPHA) IS CRITICAL FOR GRANULOPOIESIS/

Cytokines stimulate granulopoiesis through signaling via receptors who se expression is controlled by lineage-specific transcription factors. Previously, we demonstrated that granulocyte colony-stimulating facto r (G-CSF) receptor mRNA was undetectable and granulocyte maturation bl ocked in CCAAT enhancer binding protein or (C/EBP alpha)-deficient mic e. This phenotype is distinct from that of G-CSF receptor(-/-) mice, s uggesting that other genes are likely to be adversely affected by loss of C/EBP alpha. Here we demonstrate loss of interleukin 6 (IL-6) rece ptor 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 trans duction of G-CSF receptors, demonstrating that loss of both of these r eceptors contributes to the absolute block in granulocyte maturation o bserved in C/EBP alpha-deficient hematopoietic cells. The results of t hese and other studies suggest that additional C/EBP alpha target gene s, possibly other cytokine receptors, are also important for the block in granulocyte differentiation observed in vivo in C/EBP alpha-defici ent mice.