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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-02-0603. This Article Full Text (PDF) All Versions of this Article: 2002-02-0603v1 101/1/194    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ducoroy, P. Articles by Solary, E. Search for Related Content PubMed PubMed Citation Articles by Ducoroy, P. Articles by Solary, E. Social Bookmarking                   What's this? Submitted February 26, 2002 Accepted August 1, 2002 LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level Patrick Ducoroy, Olivier Micheau, Sylvain Perruche, Laurence Dubrez-Daloz, Daniel de Fornel, Patrick Dutartre, Philippe Saas, and Eric Solary* Faculties of Medicine and Pharmacy, INSERM U517, IFR 100, Dijon, France Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland Etablissement Francais du Sang, Bourgogne Franche-Comte, INSERM E0119, Besancon, France Research, Fournier SA, Daix, France * Corresponding author; email: esolary{at}u-bourgogne.fr. The deoxyspergualin derivative LF 15-0195 has demonstrated some efficacy in animal models of auto-immune and graft-versus-host diseases and is currently tested in clinics. The molecular mechanisms of LF 15-0195 immunosuppressive activity remained unknown. We show that exposure to LF 15-0195 sensitizes Jurkat T cells to apoptosis induced by an agonistic anti-CD95 antibody (CH11 clone) and by the cytokine TRAIL. LF 15-0195 does not demonstrate any significant effect on the post-mitochondrial activation of caspases, nor it modifies overall expression of CD95, FADD and procaspase-8. The compound facilitates the recruitment of these molecules to the death-inducing signaling complex (DISC) and enhances caspase-8 and -10 activation, thus increasing cytochrome c and DIABLO/Smac mitochondrial release. LF 15-0195 also sensitizes Jurkat T cells to CD3-mediated apoptosis, an in vitro model for activation-induced T cell death (AICD). LF 15-0195-mediated sensitization to AICD was further confirmed in human peripheral T cells exposed to anti-CD3 antibodies, then cultured in the presence of IL-2. In these cells, LF 15-0195 increased apoptosis triggered by either anti-CD95 antibodies or CD3 restimulation whereas no effect was observed on so-called "passive apoptosis." Lastly, in bone-marrow recipient mice, LF 15-0195 enhanced allogeneic donor T cell death, which required a functional CD95 pathway. These results suggest that LF 15-0195 sensitizes T cells to AICD by increasing caspase activation at the DISC level in response to CD95 engagement. This original mechanism, together with LF 15-0195 efficacy in various disease models, make this compound a promising immunosuppressive drug. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Engedal, P. Auberger, and H. K. Blomhoff Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly J. Leukoc. Biol., March 1, 2009; 85(3): 469 - 480. [Abstract] [Full Text] [PDF] L. Le Berre, S. 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Gambert, M. Cherkaoui-Malki, B. Jannin, L. Dubrez-Daloz, N. Latruffe, et al. Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells J. Biol. Chem., October 17, 2003; 278(42): 41482 - 41490. [Abstract] [Full Text] [PDF] J. Yang, S. M. Bernier, T. E. Ichim, M. Li, X. Xia, D. Zhou, X. Huang, G. H. Strejan, D. J. White, R. Zhong, et al. LF15-0195 generates tolerogenic dendritic cells by suppression of NF-{kappa}B signaling through inhibition of IKK activity J. Leukoc. Biol., September 1, 2003; 74(3): 438 - 447. [Abstract] [Full Text] [PDF]

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