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TGF-β induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL

By L.C. Spender, D.I. O'Brien, D. Simpson, D. Dutt, C.D. Gregory, M.J. Allday, L.J. Clark and G.J. Inman


Transforming growth factor-β (TGF-β) potently induces apoptosis in Burkitt's lymphoma (BL) cell lines and in explanted primary human B lymphocytes. The physiological relevance and mechanism of TGF-β-mediated apoptosis induction in these cells remains to be determined. Here we demonstrate the requirement for TGF-β-mediated regulation of BIK and BCL-XL to activate an intrinsic apoptotic pathway in centroblastic BL cells. TGF-β directly induced transcription of BIK and a consensus Smad-binding element identified in the BIK promoter recruits TGF-β-activated Smad transcription factor complexes in vivo. TGF-β also transcriptionally repressed expression of the apoptosis inhibitor BCL-XL. Inhibition of BCL-XL sensitised BL cells to TGF-β-induced apoptosis whereas overexpression of BCL-XL or suppression of BIK by shRNA, diminished TGF-β-induced apoptosis. BIK and BCL-XL were also identified as TGF-β target genes in purified normal human centroblast B cells and immunohistochemical analyses of tonsil tissue revealed widespread TGF-β receptor-regulated Smad activation and a focal pattern of BIK expression. Furthermore, using a selective inhibitor of the TGF-β receptor we provide evidence that autocrine TGF-β signalling through ALK5 contributes to the default apoptotic programme in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-β may act as a physiological mediator of human germinal centre homoeostasis by regulation of BIK and BCL-XL

Publisher: 'Springer Science and Business Media LLC'
Year: 2009
DOI identifier: 10.1038/cdd.2008.183
OAI identifier:
Provided by: Enlighten
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