Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma

Daniel Salamon; Monika Adori; Minghui He; Peter Bönelt; Eva Severinson; Lorand L Kis; Liang Wu; Dorina Ujvari; Benjamin Leveau; Noemi Nagy; George Klein; Eva Klein

doi:10.1016/j.cyto.2011.12.001

Type I interferons directly down-regulate BCL-6 in primary and transformed germinal center B cells: differential regulation in B cell lines derived from endemic or sporadic Burkitt's lymphoma

Cytokine. 2012 Mar;57(3):360-71. doi: 10.1016/j.cyto.2011.12.001. Epub 2011 Dec 26.

Authors

Daniel Salamon¹, Monika Adori, Minghui He, Peter Bönelt, Eva Severinson, Lorand L Kis, Liang Wu, Dorina Ujvari, Benjamin Leveau, Noemi Nagy, George Klein, Eva Klein

Affiliation

¹ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels vag 16, SE-171 77 Stockholm, Sweden. Daniel.Salamon@ki.se

PMID: 22204827
DOI: 10.1016/j.cyto.2011.12.001

Abstract

Type I interferons (IFN) exert multiple effects on both the innate and adaptive immune system in addition to their antiviral and antiproliferative activities. Little is known, however about the direct effects of type I IFNs on germinal center (GC) B cells, the central components of adaptive B cell responses. We used Burkitt's lymphoma (BL) lines, as a model system of normal human GC B cells, to examine the effect of type I IFNs on the expression of BCL-6, the major regulator of the GC reaction. We show that type I IFNs, but not IFNγ, IL-2 and TNFα rapidly down-regulate BCL-6 protein and mRNA expression, in cell lines derived from endemic, but not from sporadic BL. IFNα-induced down-regulation is specific for BCL-6, independent of Epstein-Barr virus and is not accompanied by IRF-4 up-regulation. IFNα-induced BCL-6 mRNA down-regulation does not require de novo protein synthesis and is specifically inhibited by piceatannol. The proteasome inhibitor MG132 non-specifically prevents, while inhibitors of alternate type I IFN signaling pathways do not inhibit IFNα-induced BCL-6 protein downregulation. We validate our results with showing that IFNα rapidly down-regulates BCL-6 mRNA in purified mouse normal GC B cells. Our results identify type I IFNs as the first group of cytokines that can down-regulate BCL-6 expression directly in GC B cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
B-Lymphocytes / drug effects
B-Lymphocytes / metabolism*
Burkitt Lymphoma / immunology
Burkitt Lymphoma / pathology*
Burkitt Lymphoma / virology
Cell Line, Transformed
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Down-Regulation / drug effects*
Gene Expression Regulation, Neoplastic / drug effects
Germinal Center / cytology*
Herpesvirus 4, Human / drug effects
Herpesvirus 4, Human / immunology
Humans
Interferon Regulatory Factors / metabolism
Interferon-alpha / pharmacology*
Interferon-gamma / pharmacology
Interleukin-2 / pharmacology
Kinetics
Leupeptins / pharmacology
Mice
Protein Biosynthesis / drug effects
Proto-Oncogene Proteins c-bcl-6
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins
Signal Transduction / drug effects
Stilbenes / pharmacology
Transcription Factors / metabolism
Tumor Necrosis Factor-alpha / pharmacology

Substances

Adaptor Proteins, Signal Transducing
BCL6 protein, human
Bcl6 protein, mouse
DNA-Binding Proteins
IFIT1 protein, human
Interferon Regulatory Factors
Interferon-alpha
Interleukin-2
Leupeptins
Proto-Oncogene Proteins c-bcl-6
RNA, Messenger
RNA-Binding Proteins
Stilbenes
Transcription Factors
Tumor Necrosis Factor-alpha
interferon regulatory factor-4
3,3',4,5'-tetrahydroxystilbene
Interferon-gamma
benzyloxycarbonylleucyl-leucyl-leucine aldehyde