Skip to main content
Log in

Macrophage-Specific Gene Expression: Current Paradigms and Future Challenges

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Cells of the mononuclear phagocyte lineage include macrophages, microglia, osteoclasts, and myeloid dendritic cells. These cell types are all derived from blood monocytes, which are the product of hematopoietic stem cell differentiation. In this review we use specific examples of macrophage-expressed genes to illustrate potential regulatory strategies for directing macrophage-specific gene expression. The examples we have chosen—the human c-fes gene, the murinespi-1 (PU.1) gene, the human RANTES promoter, and the human CD68 gene—illustrate different aspects of constitutive and inducible gene expression in macrophages. One important challenge for future work in this field will be to identify the molecular events that dictate lineage decisions during the differentiation of mononuclear phagocytes from hematopoietic progenitor cells. Another important goal will be to understand how groups of macrophage genes are coordinately expressed in response to physiological, immuno-logical, and inflammatory stimuli. A better understanding of macrophage gene expression may find application in gene therapy, genetic vaccination, and the development of new antiinflammatory drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Baltimore D. Our genome unveiled.Nature. 2001;409:814–816.

    Article  CAS  PubMed  Google Scholar 

  2. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity.Immunity. 2000;12:121–127.

    Article  CAS  PubMed  Google Scholar 

  3. Lin HH, Stacey M, Hamann J, Gordon S, McKnight AJ. Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97.Genomics. 2000;67:188–200.

    Article  CAS  PubMed  Google Scholar 

  4. Dillon N, Sabbattini P. Functional gene expression domains: defining the functional unit of eukaryotic gene regulation.Bioessays. 2000;22:657–665.

    Article  CAS  PubMed  Google Scholar 

  5. Verrijzer CP, Tjian R. TAFs mediate transcriptional activation and promoter selectivity.Trends Biochem Sci. 1996;21:338–342.

    Article  CAS  PubMed  Google Scholar 

  6. Berk AJ. TBP-like factors come into focus.Cell. 2000;103:5–8.

    Article  CAS  PubMed  Google Scholar 

  7. Javahery R, Khachi A, Lo K, Zenzie-Gregory B, Smale ST. DNA sequence requirements for transcriptional initiator activity in mammalian cells.Mol Cell Biol. 1994;14:116–127.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Smale ST, Baltimore D. The “initiator” as a transcription control element.Cell. 1989;57:103–113.

    Article  CAS  PubMed  Google Scholar 

  9. Suzuki Y, Tsunoda T, Sese J, et al. Identification and characterization of the potential promoter regions of 1031 kinds of human genes.Genome Res. 2001;11:677–684.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Clarke S, Gordon S. Myeloid-specific gene expression.J Leukoc Biol. 1998;63:153–168.

    Article  CAS  PubMed  Google Scholar 

  11. Tenen DG, Hromas R, Licht JD, Zhang DE. Transcription factors, normal myeloid development, and leukemia.Blood. 1997;90: 489–519.

    CAS  PubMed  Google Scholar 

  12. Ross IL, Yue X, Ostrowski MC, Hume DA. Interaction between PU.1 and another Ets family transcription factor promotes macro-phage-specific basal transcription initiation.J Biol Chem. 1998;273:6662–6669.

    Article  CAS  PubMed  Google Scholar 

  13. McKnight SL, Gavis ER. Expression of the herpes thymidine kinase gene inXenopus laevis oocytes: an assay for the study of deletion mutants constructed in vitro.Nucleic Acids Res. 1980;8:5931–5948.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Myers RM, Tilly K, Maniatis T. Fine structure genetic analysis of a beta-globin promoter.Science. 1986;232:613–618.

    Article  CAS  PubMed  Google Scholar 

  15. Kadonaga JT, Carner KR, Masiarz FR., Tjian R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain.Cell. 1987;51:1079–1090.

    Article  CAS  PubMed  Google Scholar 

  16. Kadonaga JT, Courey AJ, Ladika J, Tjian R. Distinct regions of Sp1 modulate DNA binding and transcriptional activation.Science. 1988;242:1566–1570.

    Article  CAS  PubMed  Google Scholar 

  17. Lemon B, Tjian R. Orchestrated response: a symphony of transcription factors for gene control.Genes Dev. 2000;14:2551–2569.

    Article  CAS  PubMed  Google Scholar 

  18. Smale ST. Core promoters: active contributors to combinatorial gene regulation.Genes Dev. 2001;15:2503–2508.

    Article  CAS  PubMed  Google Scholar 

  19. Banerji J, Rusconi S, Schaffner W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences.Cell. 1981;27:299–308.

    Article  CAS  PubMed  Google Scholar 

  20. Dorsch-Hasler K, Keil GM, Weber F, Jasin M, Schaffner W, Koszi-nowski UH. A long and complex enhancer activates transcription of the gene coding for the highly abundant immediate early mRNA in murine cytomegalovirus.Proc Natl Acad Sci U S A. 1985;82:8325–8329.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Schaffner W. Gene regulation: a hit-and-run mechanism for transcriptional activation?Nature. 1988;336:427–428.

    Article  CAS  PubMed  Google Scholar 

  22. Fry CJ, Peterson CL. Chromatin remodeling enzymes: who’s on first?Curr Biol. 2001;11:R185-R197.

    Article  CAS  PubMed  Google Scholar 

  23. Rosenfeld MG, Glass CK. Coregulator codes of transcriptional regulation by nuclear receptors.J Biol Chem. 2001;276:36865–3688.

    Article  CAS  PubMed  Google Scholar 

  24. Kollias G, Hurst J, deBoer E, Grosveld F. The human beta-globin gene contains a downstream developmental specific enhancer.Nucleic Acids Res. 1987;15:5739–5747.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Grosveld F, van Assendelft GB, Greaves DR, Kollias G. Position-independent, high-level expression of the human beta globin gene in transgenic mice.Cell. 1987;51:975–985.

    Article  CAS  PubMed  Google Scholar 

  26. Talbot DJ, Collis P, Antoniou M, Vidal M, Grosveld F, Greaves DR. A dominant control region from the human beta-globin locus conferring integration site- independent gene expression.Nature. 1989;338:352- 355.

    Article  CAS  PubMed  Google Scholar 

  27. Blom van Assendelft G, Hanscombe O, Grosveld F, Greaves DR. The beta-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner.Cell. 1989;56:969–977.

    Article  Google Scholar 

  28. Orkin SH. Globin gene regulation and switching: circa 1990.Cell. 1990;63:665–672.

    Article  CAS  PubMed  Google Scholar 

  29. Greaves DR, Wilson FD, Lang G, Kioussis D. Human CD2 3′ flanking sequences confer high-level, T-cell specific, position independent gene expression in transgenic mice.Cell. 1989;56:979–986.

    Article  CAS  PubMed  Google Scholar 

  30. Diaz P, Cado D, Winoto A. A locus control region in the T cell receptor alpha/delta locus.Immunity. 1994;1:207–217.

    Article  CAS  PubMed  Google Scholar 

  31. Madisen L, Groudine M. Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt’s lymphoma cells.Genes Dev. 1994;8:2212–2226.

    Article  CAS  PubMed  Google Scholar 

  32. Sabbattini P, Georgiou A, Sinclair C, Dillon N. Analysis of mice with single and multiple copies of transgenes reveals a novel arrangement for the lambda5-VpreB1 locus control region.Mol Cell Biol. 1999;19:671–679.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Aronow BJ, Silbiger RN, Dusing MR, et al. Functional analysis of the human adenosine deaminase gene thymic regulatory region and its ability to generate position-independent transgene expression.Mol Cell Biol. 1992;12:4170–4185.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Grosveld F. Activation by locus control regions?Curr Opin Genet Dev. 1999;9:152–157.

    Article  CAS  PubMed  Google Scholar 

  35. Festenstein R, Kioussis D. Locus control regions and epigenetic chromatin modifiers.Curr Opin Genet Dev. 2000;10:199–203.

    Article  CAS  PubMed  Google Scholar 

  36. Engel JD, Tanimoto K. Looping, linking, and chromatin activity: new insights into beta-globin locus regulation.Cell. 2000;100:499–502.

    Article  CAS  PubMed  Google Scholar 

  37. Greer P, Maltby V, Rossant J, Bernstein A, Pawson T. Myeloid expression of the human c-fps/c-fes proto-oncogene in transgenic mice.Mol Cell Biol. 1990;10:2521–2527.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Heydemann A, Juang G, Hennessy K, Parmacek MS, Simon MC. The myeloid cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor.Mol Cell Biol. 1996;16:1676–1686.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Heydemann A, Boehmler JH, Simon MC. Expression of two myeloid cell-specific genes requires the novel transcription factor, c-fes expression factor.J Biol Chem. 1997;272:29527–29537.

    Article  CAS  PubMed  Google Scholar 

  40. Heydemann A, Warming S, Clendenin C, Sigrist K, Hjorth JP, Simon MC. A minimal c-fes cassette directs myeloid-specific expression in transgenic mice.Blood. 2000;96:3040–3048.

    CAS  PubMed  Google Scholar 

  41. Chen HM, Zhang P, Voso MT, et al. Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B.Blood. 1995;85:2918–2928.

    CAS  PubMed  Google Scholar 

  42. van Dijk TB, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP. The role of transcription factor PU.1 in the activity of the intronic enhancer of the eosinophil-derived neurotoxin (RNS2) gene.Blood. 1998;91:2126–2132.

    PubMed  Google Scholar 

  43. Henkel GW, McKercher SR, Yamamoto H, Anderson KL, Oshima RG, Maki RA. PU.1 but not ets-2 is essential for macrophage development from embryonic stem cells.Blood. 1996;88:2917–2926.

    CAS  PubMed  Google Scholar 

  44. Anderson KL, Perkin H, Surh CD, Venturini S, Maki RA, Torbett BE. Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor-derived dendritic cells.J Immunol. 2000;164:1855–1861.

    Article  CAS  PubMed  Google Scholar 

  45. Simon MC. PU.1 and hematopoiesis: lessons learned from gene targeting experiments.Semin Immunol. 1998;10:111–118.

    Article  CAS  PubMed  Google Scholar 

  46. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages.Science. 1994;265:1573–1577.

    Article  CAS  PubMed  Google Scholar 

  47. McKercher SR, Torbett BE, Anderson KL, et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 1996;15:5647–5658.

    CAS  Google Scholar 

  48. Zhang P, Zhang X, Iwama A, et al. PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding.Blood. 2000;96:2641–2648.

    CAS  PubMed  Google Scholar 

  49. Chen H, Ray-Gallet D, Zhang P, et al. PU.1 (Spi-1) autoregulates its expression in myeloid cells.Oncogene. 1995;11:1549–1560.

    CAS  PubMed  Google Scholar 

  50. Chen H, Zhang P, Radomska HS, Hetherington CJ, Zhang DE, Tenen DG. Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter.J Biol Chem. 1996;271:15743–15752.

    Article  CAS  PubMed  Google Scholar 

  51. Li Y, Okuno Y, Zhang P, et al. Regulation of the PU.1 gene by distal elements.Blood. 2001;98:2958–2965.

    Article  CAS  PubMed  Google Scholar 

  52. Philipsen S, Talbot D, Fraser P, Grosveld F. The beta-globin dominant control region: hypersensitive site 2. EMBO J. 1990;9:2159–2167.

    Article  PubMed Central  CAS  Google Scholar 

  53. Talbot D, Philipsen S, Fraser P, Grosveld F. Detailed analysis of the site 3 region of the human beta-globin dominant control region. EMBO J. 1990;9:2169–2177.

    Article  PubMed Central  CAS  Google Scholar 

  54. Schall TJ, Jongstra J, Dyer BJ, et al. A human T cell-specific molecule is a member of a new gene family.J Immunol. 1988;141:1018–1025.

    CAS  PubMed  Google Scholar 

  55. Greaves DR, Schall TJ. Chemokines and myeloid cell recruitment.Microbes Infect. 2000;2:331–336.

    Article  CAS  PubMed  Google Scholar 

  56. Marfaing-Koka A, Devergne O, Gorgone G, et al. Regulation of the production of the RANTES chemokine by endothelial cells: synergistic induction by IFN-gamma plus TNF-alpha and inhibition by IL-4 and IL-13.J Immunol. 1995;154:1870–1878.

    CAS  PubMed  Google Scholar 

  57. Rathanaswami P, Hachicha M, Sadick M, Schall TJ, McColl SR. Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts: differential regulation of RANTES and inter-leukin-8 genes by inflammatory cytokines.J Biol Chem. 1993;268:5834–5839.

    CAS  PubMed  Google Scholar 

  58. Zhang L, Redington AE, Holgate ST. RANTES: a novel mediator of allergic inflammation?Clin Exp Allergy. 1994;24:899–904.

    Article  CAS  PubMed  Google Scholar 

  59. Ehrt S, Schnappinger D, Bekiranov S, et al. Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide syn-thase-2 and phagocyte oxidase.J Exp Med. 2001;194:1123–1140.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Song A, Nikolcheva T, Krensky AM. Transcriptional regulation of RANTES expression in T lymphocytes.Immunol Rev. 2000;177:236–245.

    Article  CAS  PubMed  Google Scholar 

  61. Boehlk S, Fessele S, Mojaat A, et al. ATF and Jun transcription factors, acting through an Ets/CRE promoter module, mediate lipopolysaccharide inducibility of the chemokine RANTES in monocytic Mono Mac 6 cells.Eur J Immunol. 2000;30:1102–1112.

    Article  CAS  PubMed  Google Scholar 

  62. Fessele S, Boehlk S, Mojaat A, et al. Molecular and in silico characterization of a promoter module and C/EBP element that mediate LPS-induced RANTES/CCL5 expression in monocytic cells. FASEB J. 2001;15:577–579.

    Article  CAS  PubMed  Google Scholar 

  63. Fessele S, Maier H, Zischek C, Nelson PJ, Werner T. Regulatory context is a crucial part of gene function.Trends Genet. 2002;18:60–63.

    Article  CAS  PubMed  Google Scholar 

  64. Pulford KA, Sipos A, Cordell JL, Stross WP, Mason DY. Distribution of the CD68 macrophage/myeloid associated antigen.Int Immunol. 1990;2:973–980.

    Article  CAS  PubMed  Google Scholar 

  65. Holness CL, Simmons DL. Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins.Blood. 1993;81:1607–1613.

    CAS  PubMed  Google Scholar 

  66. Ramprasad MP, Terpstra V, Kondratenko N, Quehenberger O, Steinberg D. Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein.Proc Natl Acad Sci U S A. 1996;93:14833–14838.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Ramprasad MP, Fischer W, Witztum JL, Sambrano GR, Quehen-berger O, Steinberg D. The 94- to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68.Proc Natl Acad Sci U S A. 1995;92:9580–9584.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Jones E, Quinn CM, See CG, et al. The linked human elongation initiation factor 4A1 (EIF4A1) and CD68 genes map to chromosome 17p13.Genomics. 1998;53:248–250.

    Article  CAS  PubMed  Google Scholar 

  69. Miyashita A, Shimizu N, Endo N, et al. Five different genes, Eif4a1, Cd68, Supl15H and Fxr2h, are clustered in a 40 kb region of mouse chromosome 11.Gene. 1999;237:53–60.

    Article  CAS  PubMed  Google Scholar 

  70. Greaves DR, Quinn CM, Seldin MF, Gordon S. Functional comparison of the murine macrosialin and human CD68 promoters in macrophage and non macrophage cell lines.Genomics. 1998;54:165–168.

    Article  CAS  PubMed  Google Scholar 

  71. Li AC, Guidez FR, Collier JG, Glass CK. The macrosialin promoter directs high levels of transcriptional activity in macrophages dependent on combinatorial interactions between PU.1 and c-Jun.J Biol Chem. 1998;273:5389–5399.

    Article  CAS  PubMed  Google Scholar 

  72. Gough PJ, Gordon S, Greaves DR. The use of human CD68 transcriptional regulatory sequences to direct high level expression of scavenger receptor SR-A in macrophages in vitro and in vivo.Immunology. 2001;103:351–361.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Lang R, Rutschman RL, Greaves DR, Murray PJ. Autocrine deactivation of macrophages in transgenic mice constitutively overex-pressing IL-10 under control of the human CD68 promoter.J Immunol. 2002;168:3402–3411.

    Article  CAS  PubMed  Google Scholar 

  74. Hashimoto S, Suzuki T, Dong HY, et al. Serial analysis of gene expression in human monocytes and macrophages.Blood. 1999;94:837–844.

    CAS  PubMed  Google Scholar 

  75. Hashimoto SI, Suzuki T, Nagai S, Yamashita T, Toyoda N, Mat-sushima K. Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression.Blood. 2000;96:2206–2214.

    CAS  PubMed  Google Scholar 

  76. Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components.Science. 2001;294:870–875.

    Article  CAS  PubMed  Google Scholar 

  77. Shiffman D, Mikita T, Tai JT, et al. Large scale gene expression analysis of cholesterol-loaded macrophages.J Biol Chem. 2000;275:37324–37332.

    Article  CAS  PubMed  Google Scholar 

  78. DeKoter RP, Singh H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1.Science. 2000;288:1439–1441.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David R. Greaves.

About this article

Cite this article

Greaves, D.R., Gordon, S. Macrophage-Specific Gene Expression: Current Paradigms and Future Challenges. Int J Hematol 76, 6–15 (2002). https://doi.org/10.1007/BF02982713

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02982713

Key words

Navigation