C EBP-EPSILON IS A MYELOID-SPECIFIC ACTIVATOR OF CYTOKINE, CHEMOKINE,AND MACROPHAGE-COLONY-STIMULATING FACTOR-RECEPTOR GENES/

C/EBP epsilon is a member of the CCAAT/enhancer binding protein family of basic region/leucine zipper transcriptional activators. The C/EBP epsilon protein is highly conserved between rodents and humans, and it s domain structure is very similar to C/EBP alpha, In mice C/EBP epsil on mRNA is only detected in hematopoietic tissues, including embryonic liver and adult bone marrow and spleen. Within the hematopoietic syst em, C/EBP epsilon is expressed primarily in myeloid cells, including p romyelocytes, myelomonocytes, and their differentiated progeny. To ide ntify potential functions of C/EBP epsilon, cell lines overexpressing the C/EBP epsilon protein were generated in the P388 lymphoblastic cel l line. In contrast to the parental cell line, C/EBPE-expressing cell lines displayed lipopolysaccharide-inducible expression of the interle ukin-6 and monocyte chemoattractant protein 1 (MCP-1) genes as well as elevated basal expression of the MIP-1 alpha and MIP-1 beta chemokine genes. In the EML-C1 hematopoietic stem cell line, C/EBP epsilon mRNA levels increased as the cells progressed along the myeloid lineage, j ust preceding activation of the gene encoding the receptor for macroph age-colony-stimulating factor (M-CSFR). M-CSFR expression was stimulat ed in C/EBP epsilon-expressing P388 cell lines, when compared with eit her the parental P388 cells or P388 cell lines expressing either C/EBP alpha or C/EBP beta, These results suggest that C/EBP epsilon may be an important regulator of differentiation of a subset of myeloid cell types and may also participate in the regulation of cytokine gene expr ession in mature cells.