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.
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.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels vag 16, SE-171 77 Stockholm, Sweden. Daniel.Salamon@ki.se
Daniel
D
Salamon
Monika
M
Adori
Minghui
M
He
Peter
P
Bönelt
Eva
E
Severinson
Lorand L
LL
Kis
Liang
L
Wu
Dorina
D
Ujvari
Benjamin
B
Leveau
Noemi
N
Nagy
George
G
Klein
Eva
E
Klein
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology* / Q000821:virology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018858:Germinal Center / Q000166:cytology*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000276:immunology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099218:Interferon Regulatory Factor-4
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D007371:Interferon-gamma; D007376:Interleukin-2; D007976:Leupeptins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D013267:Stilbenes; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099218:Interferon Regulatory Factor-4; C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; C484290:IFIT1 protein, human; C041525:3,3',4,5'-tetrahydroxystilbene; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde