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CD68 is a transmembrane glycoprotein expressed in all cells of the mononuclear phagocyte lineage including monocytes and tissue resident macrophages. Deletion analysis of the 5'-flanking sequences of the gene demonstrated that the proximal -150-bp sequence of the CD68 promoter exhibits high level promoter activity in macrophages. Mutations that abolish Ets factor binding at positions -106 and -89 reduce promoter activity in macrophages to 12 and 30%, respectively. Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro. Furthermore, chromatin immunoprecipitation experiments confirm that Elf-1 and PU.1 associate with the CD68 proximal promoter in vivo in THP-1 cells. PU.1 does not bind to the CD68 promoter alone but instead forms heterocomplexes with members of the interferon regulatory factor family (IRF) including IRF-4 and IRF-8. IRF-4 and IRF-8 typically mediate transcriptional activation when associated with PU.1 on composite elements. However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. Chromatin immunoprecipitation data reveal that neither IRF-4 nor IRF-8 associate with the CD68 proximal promoter in macrophages in vivo but IRF-4 is associated with the promoter in B lymphocytes. We propose that expression of CD68 in myeloid cells requires the Ets transcription factors Elf-1 and PU.1 and CD68 expression is down-regulated in lymphoid cells by combinatorial interactions between PU.1 and IRF-4.

Original publication

DOI

10.1074/jbc.M212150200

Type

Journal article

Journal

J Biol Chem

Publication Date

13/06/2003

Volume

278

Pages

21909 - 21919

Keywords

Amino Acid Motifs, Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, B-Lymphocytes, Base Sequence, Binding Sites, Blotting, Western, COS Cells, Cell Line, DNA-Binding Proteins, Down-Regulation, Genes, Reporter, Genetic Vectors, HL-60 Cells, Humans, Interferon Regulatory Factors, Lymphocytes, Macrophages, Mice, Models, Genetic, Molecular Sequence Data, Mutation, Nuclear Proteins, Plasmids, Polymerase Chain Reaction, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, RNA, Messenger, Repressor Proteins, Time Factors, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured, U937 Cells