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Bisindolylmaleimide VIII facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases

Abstract

Fas-mediated apoptosis is essential for the elimination of cells, and impaired apoptosis can have severe detrimental consequences. Bisindolylmaleimide VIII potentiated Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-4 T cells, both of which were devoid of apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII, and in Jurkat and CEM-6 T cells, which showed slight and moderate apoptotic responses, respectively, to low levels of Fas stimulation. Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was selective for activated, rather than non-activated, T cells, and was Fas-dependent, as it was not observed in T cells from Fas-deficient lpr/lpr mice. Administration of bisindolylmaleimide VIII to rats during autoantigen stimulation prevented the development of symptoms of T cell-mediated autoimmune diseases in two models, the Lewis rat model of experimental allergic encephalitis and the Lewis adjuvant arthritis model. Thus, the use of agents such as bisindolylmaleimide VIII may be therapeutically useful for supporting more effective elimination of detrimental cells through enhancement of Fas-dependent apoptosis signaling.

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Figure 1: Bisindolylmaleimide VIII enhances apoptosis induced by anti-Fas antibody in 1321N1 cells.
Figure 2: Apoptosis analysis of 1321N1 cells.
Figure 3: Dose dependencies of bisindolylmaleimide VIII and anti-Fas antibody on potentiation of apoptosis.
Figure 4: Effect of bisindolylmaleimide VIII on apoptosis of 1321N1 cells induced by TNF-α, dexamathsone or gamma-irradiation.
Figure 5: Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII in human T-cell lines.
Figure 6: Bisindolylmaleimide VIII enhances activation-induced cell death in T cells in a Fas-dependent fashion.
Figure 7: Bisindolylmaleimide VIII inhibits antigen-specific T-cell response.

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Acknowledgements

We thank W.J. Koopman and R.P. Kimberly for their critical comments and F. Hunter for editing the manuscript. T.Z. is supported by the Arthritis Foundation, the Juvenile Diabetes Foundation, a grant from the NIH (AR44982), and a grant from Sankyo (Japan). R.S.J. is supported by grants from the NIH (MH38752 and AG06569).

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Correspondence to Tong Zhou or Richard S. Jope.

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Zhou, T., Song, L., Yang, P. et al. Bisindolylmaleimide VIII facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases. Nat Med 5, 42–48 (1999). https://doi.org/10.1038/4723

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