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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Transforming growth factor-beta (TGF-beta) potently induces apoptosis in Burkitt's lymphoma (BL) cell lines and in explanted primary human B lymphocytes. The physiological relevance and mechanism of TGF-beta-mediated apoptosis induction in these cells remains to be determined. Here we demonstrate the requirement for TGF-beta-mediated regulation of BIK and BCL-X(L) to activate an intrinsic apoptotic pathway in centroblastic BL cells. TGF-beta directly induced transcription of BIK and a consensus Smad-binding element identified in the BIK promoter recruits TGF-beta-activated Smad transcription factor complexes in vivo. TGF-beta also transcriptionally repressed expression of the apoptosis inhibitor BCL-X(L). Inhibition of BCL-X(L) sensitised BL cells to TGF-beta-induced apoptosis whereas overexpression of BCL-X(L) or suppression of BIK by shRNA, diminished TGF-beta-induced apoptosis. BIK and BCL-X(L) were also identified as TGF-beta target genes in purified normal human centroblast B cells and immunohistochemical analyses of tonsil tissue revealed widespread TGF-beta receptor-regulated Smad activation and a focal pattern of BIK expression. Furthermore, using a selective inhibitor of the TGF-beta receptor we provide evidence that autocrine TGF-beta signalling through ALK5 contributes to the default apoptotic programme in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-beta may act as a physiological mediator of human germinal centre homoeostasis by regulation of BIK and BCL-X(L).
Original languageEnglish
Pages (from-to)593-602
Number of pages10
JournalCell Death & Differentiation (CDD)
Issue number4
Publication statusPublished - Apr 2009

Keywords / Materials (for Non-textual outputs)

  • TGF-β
  • apoptosis
  • centroblast
  • BIK
  • BCL-XL


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