Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: Specific regulation of I epsilon transcription and immunoglobulinE switching

The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor tha t is expressed in B cells and a subset of CD4(+) T cells within germinal ce nters. Recent evidence suggests that BCL-6 can act as a sequence-specific r epressor 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)-induce d Stat6 (signal transducers and activators of transcription) signaling mole cule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind , with different affinities, to several DNA elements recognized by Stat6. E xpression of BCL-6 can repress the IL-4 dependent induction of immunoglobul in (Ig) germ line epsilon transcripts, but does not repress the IL-4 induct ion of CD23 transcripts. Consistent with the role of BCL-6 in modulating tr anscription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. The se animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulatio n of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signali ng. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.