TGF-β induces apoptosis in human B cells via transcriptional regulation of BIK and BCL-X(L)

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-X(L) 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-X(L). Inhibition of BCL-X(L) sensitised BL cells to TGF-β-induced apoptosis while overexpression of BCL-X(L) or suppression of BIK by shRNA, diminished TGF-β-induced apoptosis. BIK and BCL-X(L) 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 signaling through ALK5 contributes to the default apoptotic program in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-β may act as a physiological mediator of human germinal centre homeostasis via regulation of BIK and BCL-X(L).