Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

BCL-6 regulates chemokine gene transcription in macrophages

Nature Immunology volume 1, pages 214–220 (2000)Cite this article

Abstract

The transcriptional repressor protein BCL-6, implicated in the pathogenesis of B cell lymphoma, regulates lymphocyte differentiation and inflammation. We investigated the mechanism for the T helper cell subset 2 (TH2)-type inflammation that occurs in BCL-6−/− mice. Using chimeric mice we found that the TH2-type inflammation is dependent upon nonlymphoid cells. We identified three chemokines, MCP-1, MCP-3 and MRP-1, which are negatively regulated by BCL-6 in macrophages. Promoter analysis revealed that BCL-6 is a potent repressor of MCP-1 transcription. Our results provide a mechanism for the regulation of TH2-type inflammation by BCL-6 and link TH2 differentiation to innate immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inflammatory wild-type disease in BCL-6−/− and chimeric BCL-6−/− mice.
Figure 2: Chemokine gene expression in wild-type (WT) and BCL-6−/− knockout (−/−) macrophages.
Figure 3: Cytokine secretion by stimulated wild-type and BCL-6−/− macrophages.
Figure 4: Constitutive expression of chemokines by Mac-1+ cells from BCL-6−/− spleen.
Figure 5: Analysis of chemokine RNA expression by heart tissue.
Figure 6: Gel shift analysis of BCL-6 binding sites.
Figure 7: Repression of chemokine expression by BCL-6.

Similar content being viewed by others

References

  1. Dalla-Favera, R. et al. Identification of genetic lesions associated with diffuse large-cell lymphoma. Ann. Oncol. 5, 55– 60 (1994).

    Article  PubMed  Google Scholar 

  2. Bastard, C. et al. LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients . Blood 83, 2423–2427 (1994).

    CAS  PubMed  Google Scholar 

  3. Lo Coco, F. et al. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Blood 83, 1757– 1759 (1994).

    CAS  PubMed  Google Scholar 

  4. Staudt, L. M., Dent, A. L., Shaffer, A. L. & Yu, X. Regulation of lymphocyte cell fate decisions and lymphomagenesis by BCL-6. Int. Rev. Immunol. 18, 381 (1999 ).

    Article  CAS  PubMed  Google Scholar 

  5. Kerckaert, J. P. et al. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nature Genet. 5, 66–70 (1993 ).

    Article  CAS  PubMed  Google Scholar 

  6. Ye, B. H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large- cell lymphoma. Science 262, 747– 750 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Seyfert, V. L., Allman, D., He, Y. & Staudt, L. M. Transcriptional repression by the proto-oncogene BCL-6. Oncogene 12 , 2331–2342 (1996).

    CAS  PubMed  Google Scholar 

  8. Deweindt, C. et al. The LAZ3/BCL6 oncogene encodes a sequence-specific transcriptional inhibitor: a novel function for the BTB/POZ domain as an autonomous repressing domain. Cell Growth Differ. 6, 1495– 1503 (1995).

    CAS  PubMed  Google Scholar 

  9. Chang, C. C., Ye, B. H., Chaganti, R. S. & Dalla-Favera, R. BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor . Proc. Natl Acad. Sci. USA 93, 6947– 6952 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2- type inflammation. Nature Genet. 16, 161–170 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Dent, A. L., Hu-Li, J., Paul, W. E. & Staudt, L. S. T helper type 2 inflammatory disease in the absence of IL-4 and STAT6. Proc. Natl Acad. Sci. USA 95, 13823–13828 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Rollins, B. J. Chemokines. Blood 90, 909– 928 (1997).

    CAS  PubMed  Google Scholar 

  15. Allman, D. et al. BCL-6 expression during B-cell activation. Blood 87, 5257–5268 ( 1996).

    CAS  PubMed  Google Scholar 

  16. Cattoretti, G. et al. BCL-6 protein is expressed in germinal-center B cells. Blood 86, 45–53 ( 1995).

    CAS  PubMed  Google Scholar 

  17. Onizuka, T. et al. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts . Blood 86, 28–37 (1995).

    CAS  PubMed  Google Scholar 

  18. Yamochi, T. et al. Regulation of BCL-6 gene expression in human myeloid/monocytoid leukemic cells. Leukemia 11, 694– 700 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  20. Mombaerts, P. et al. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature 360, 225–231 (1992). [Published Erratum appears in Nature 360, 491 (1992).]

    Article  CAS  PubMed  Google Scholar 

  21. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423– 426 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Fukuda, T. et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J. Exp. Med. 186, 439– 448 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schook, L. B., Albrecht, H., Gallay, P. & Jongeneel, C. V. Cytokine regulation of TNF-α mRNA and protein production by unprimed macrophages from C57Bl/6 and NZW mice. J. Leuk. Biol. 56, 514–520 (1994).

    Article  CAS  Google Scholar 

  24. Biswas, P. et al. Interleukin-6 induces monocyte chemotactic protein-1 in peripheral blood mononuclear cells and in the U937 cell line. Blood 91, 258–265 (1998).

    CAS  PubMed  Google Scholar 

  25. Zhang, S., Lukacs, N. W., Lawless, V. A., Kunkel, S. L. & Kaplan, M. H. Cutting edge: differential expression of chemokines in Th1 and Th2 cells is dependent on stat6 but not stat4. J. Immunol. 165, 10–14 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  26. Li, L. et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J. Immunol. 162, 2477–2487 (1999).

    CAS  PubMed  Google Scholar 

  27. Huynh, K. D., Fischle, W., Verdin, E. & Bardwell, V. J. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 14, 1810–1823 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gu, L. et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407 –411 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Lukacs, N. W. et al. C-C chemokines differentially alter interleukin-4 production from lymphocytes. Am J Pathol 150, 1861– 1868 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Karpus, W. J. et al. Differential CC chemokine-induced enhancement of T helper cell cytokine production. J. Immunol. 158, 4129–4136 (1997).

    CAS  PubMed  Google Scholar 

  31. Karpus, W. J. & Kennedy, K. J. MIP-1α and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. J. Leuk. Biol. 62, 681–687 (1997).

    Article  CAS  Google Scholar 

  32. Braun, M. C., Lahey, E. & Kelsall, B. L. Selective suppression of IL-12 production by chemoattractants . J. Immunol. 164, 3009– 3017 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Kapsenberg, M. L., Hilkens, C. M., Wierenga, E. A. & Kalinski, P. The paradigm of type 1 and type 2 antigen-presenting cells. Implications for atopic allergy. Clin. Exp. Aller. 29, 33 –36 (1999).

    Article  Google Scholar 

  34. Abbas, A. K., Murphy, K. M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  35. Harris, M. B. et al. Transcriptional Repression of Stat6-Dependent Interleukin-4-Induced Genes by BCL-6: Specific Regulation of Iepsilon Transcription and Immunoglobulin E Switching. Mol. Cell Biol. 19, 7264– 7275 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Friend, D. S. et al. Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype. J. Cell Biol. 135, 279–290 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  37. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. (Cold Spring Harbor Laboratory, New York, 1989).

    Google Scholar 

  38. Schreiber, E., Matthias, P., Muller, M. M. & Schaffner, W. Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res. 17, 6419 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Rice and J. Lay for assistance with cell sorting, and E. Vig for assistance with luciferase and β-galactosidase assays. Partly supported by a Research-in-Aid grant (to A.L.D.) from Indiana University-Purdue University at Indianapolis, a Biomedical Research Grant (to A.L.D.) from Indiana University School of Medicine, and NIH grant CA-37295 (to R.D.F.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine, Indianapolis , 46202, IN

    Lisa M. Toney, Jennifer A. Graf & Alexander L. Dent

  2. the Walther Cancer Institute , Indianapolis, 46208, IN, USA

    Lisa M. Toney, Jennifer A. Graf & Alexander L. Dent

  3. Institute of Cancer Genetics and Department of Pathology College of Physicians and Surgeons, Columbia University, New York , 10032, NY, USA

    Giorgio Cattoretti & Riccardo Dalla-Favera

  4. Department of Human Genetics and Molecular Biology Program, Sloan Kettering Division Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, Cornell University, 1275 York Avenue, New York, 10021, NY, USA

    Taha Merghoub & Pier-Paolo Pandolfi

  5. Department of Cell Biology and Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    B. Hilda Ye

Authors
  1. Lisa M. Toney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giorgio Cattoretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer A. Graf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taha Merghoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pier-Paolo Pandolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Riccardo Dalla-Favera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. Hilda Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexander L. Dent
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander L. Dent.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toney, L., Cattoretti, G., Graf, J. et al. BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 1, 214–220 (2000). https://doi.org/10.1038/79749

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79749

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing