Bisindolylmaleimide VIII facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases.
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-4T 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.
Zhou
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T
Department of Medicine, The University of Alabama at Birmingham, 35294, USA. tong.zhou@ccc.uab.edu
Song
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L
Yang
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P
Wang
Z
Z
Lui
D
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Jope
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D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011493:Protein Kinase C; C088060:bisindolylmaleimide