Transcriptional Repression of Stat6-Dependent Interleukin-4-Induced Genes by BCL-6: Specific Regulation of I epsilon Transcription and Immunoglobulin E Switching

• Published in: Molecular and cellular biology 1999-10, Vol.19 (10), p.7264-7275
• Main Authors: Harris, M B, Chang, C, Berton, M T, Danial, N N, Zhang, J, Kuehner, D, Ye, B H, Kvatyuk, M, Pandolfi, P P, Cattoretti, G, Favera, R D, Rothman, P B
• Format: Article
• Language: English
• ISSN: 0270-7306
• DOI: 10.1128/mcb.19.10.7264

The BCL-6 proto-oncogene encodes a POZ/zinc- finger transcription factor that is expressed in B cells and a subset of CD4 super(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6 super(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE super(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6 super(-/-) Stat6 super(-/-) mice indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.