TGF-beta 1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines

Abstract : We have previously shown that Fas-induced apoptosis is markedly enhanced by IL-7 in human pre-B but not pro-B cell lines. In addition, pre-B cell receptor (pre-BCR) ligation significantly potentiates the IL-7 effects on Fas-triggered pre-B cell death. We show herein that transforming growth factor (TGF)-beta1 sharply reduces Fas-induced death rate of pre-B but not pro-B cells. TGF-beta1 causes inhibition of Fas-mediated disruption of mitochondrial transmembrane potential and cleavage of caspase 8, Bid and caspase 3. Bcl2 expression is markedly increased in TGF-beta1-treated pre-B cells, whereas cellular FLICE-like inhibitory protein long (c-FLIPL), Bcl-XL, Bax, and Bad expression remains unchanged. TGF-beta1 causes a selective growth arrest of pre-B cells in G0/G1 phase of the cell cycle and induces a partial down-modulation of both Fas and pre-BCR expression. All TGF-beta1-mediated effects, but Bcl2 up-regulation, can be reproduced by the LY294002 phosphatidylinositol 3-kinase (Pl3K)/Akt inhibitor but not by inhibitors of the MAPK/ERK (MEK) and Janus kinase (Jak)/STAT pathways, which promote cell death. Akt phosphorylation is strongly inhibited by TGF-beta1 in pre-B but not pro-B cells and is not modified by Fas engagement. Altogether, our findings suggest that TGF-beta1 prevents Fas-induced apoptosis of pre-B lines by inhibiting Pl3K pathway and by enhancing expression of Bcl2. They also suggest that the Pl3K/Akt pathway is involved in the control of Fas and pre-BCR expression, a checkpoint in B cell development.
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https://hal.archives-ouvertes.fr/hal-02239702
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Submitted on : Thursday, August 1, 2019 - 3:50:19 PM
Last modification on : Monday, August 12, 2019 - 5:08:07 PM

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  • HAL Id : hal-02239702, version 1

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O. Lanvin, P. Guglielmi, V. Fuentes, V. Gouilleux-Gruart, C. Maziere, et al.. TGF-beta 1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines. European Journal of Immunology, Wiley-VCH Verlag, 2003, 33 (5), pp.1372--1381. ⟨hal-02239702⟩

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