Roles of Ets proteins, NF-κB and nocodazole in regulating induction of transcription of mouse germline Ig α RNA by transforming growth factor-β1

초록

Antibody class switch recombination (CSR) occurs after antigen activation of B cells. CSR is directed to specific heavy chain isotypes by cytokines and B cell activators that induce transcription from the unrearranged, or germline (GL), C<inf>H</inf> region genes. Transforming growth factor (TGF)-β1 is essential for switch recombination to IgA due to its ability to induce transcription from GL Ig α genes. It has been shown that the promoters which regulate transcription of mouse and human GL α RNAs contain a TGF-β1-responsive element that binds Smad and core binding factor (CBFα)/AML/PEBPα/Runx. They also contain other elements which bind the transcription factors CREB, BSAP and Ets family proteins. In this manuscript we demonstrate that two tandem Ets sites in the mouse GL α promoter bind the transcription factors Elf-1 and PU.1, and that the 3′ site is essential for expression of a luciferase reporter gene driven by the GL α promoter. Binding of Elf-1 to the GL α promoter is inducible by lipopolysaccharide in nuclear extracts from splenic B cells. An NF-κB site is identified, although it does not contribute to expression of the promoter in reporter gene assays. Since CSR to IgA is greatly reduced in NF-κB/p50-deficient mice, these data support the hypothesis that NF-κB has roles in switching in addition to regulation of GL transcription. Finally, we demonstrate that nocodazole, which disrupts microtubules that sequester Smad proteins in the cytoplasm, stimulates transcription from the GL α promoter.

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