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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1777-1784.
Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2004-08-3171.
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Submitted August 17, 2004
Accepted October 11, 2004
BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production
Raymond Y Yu, Xing Wang, Fiona J Pixley, J J Yu, Alexander L Dent, Hal E Broxmeyer, E R Stanley, and B H Ye*
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA
* Corresponding author; email: hye{at}aecom.yu.edu.
The transcription repressor BCL-6 is known to play critical roles in B cell lymphomagenesis, germinal center formation, and balanced Th1/Th2 differentiation. In macrophages, although BCL-6 has also been shown to regulate the expression of several chemokine genes, its function in other aspects of macrophage biology has not been studied. In addition, the precise role of BCL-6 in cell proliferation is poorly understood in general. Here we report that BCL-6-/- macrophages hyperproliferate due to an accelerated G1/S transition accompanied by increased cyclin D2 and c-myc, and decreased expression of p27. Crucial to this enhanced proliferation is spontaneous IL-6 production and STAT3 activation in BCL-6-/- macrophages. In colony forming assays, BCL-6-/- bone marrow progenitor cells form spontaneous macrophage colonies that can be inhibited by anti-IL-6 antibodies. Gene expression studies demonstrate that BCL-6 binds to several sequence motifs scattered in the IL-6 locus and can repress IL-6 transcription both in 293T cells and in macrophages. In conclusion, our results indicate that BCL-6 negatively regulates proliferation of the monocytic/macrophage lineage by suppressing an autocrine IL-6/STAT3-mediated gene expression program. Our work also suggests that BCL-6 prevents abnormal Th2 differentiation by suppressing basal-level IL-6 production in antigen presenting cells (APC).
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