C/EBP, NF-κB, and c-Ets Family Members and Transcriptional Regulation of the Cell-Specific and Inducible Macrophage Inflammatory Protein 1α Immediate-Early Gene

Abstract

Macrophage inflammatory protein 1α (MIP-1α) cytokine gene expression is restricted to a limited number of cells of hemopoietic origin and is rapidly and transiently induced by serum and endotoxin in macrophages. A single nuclear DNase I-hypersensitive site, which maps to the proximal promoter of the MIP-1α gene, was identified in macrophage cells but was absent in cells which do not express basal levels of MIP-1 alpha mRNA. The proximal promoter sequences (+36 to -220 bp) are sufficient to confer cell-specific and inducible transcription in transfection assays. In vitro DNA-binding studies revealed five major nuclear protein binding sites in the proximal promoter which bind C/EBP, NF-κB, and/or c-Ets family members. Cell-specific differences in DNA binding by members of the NF-κB and c-Ets families correlate with the cell-specificity of MIP-1α gene expression and the chromosomal conformation of the promoter. Changes in promoter binding by members of the C/EBP and NF-κB families correlate with the transcriptional up-regulation observed in serum- or endotoxin-stimulated macrophages in functional studies.