SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-06-1688. This Article Full Text (PDF) All Versions of this Article: 2002-06-1688v1 101/4/1439    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 Woltman, A. M Articles by van Kooten, C. Search for Related Content PubMed PubMed Citation Articles by Woltman, A. M Articles by van Kooten, C. Social Bookmarking                   What's this? Submitted June 7, 2002 Accepted September 17, 2002 Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells leading to apoptosis via increased p27KIP1 expression Andrea M Woltman*, Sandra W van der Kooij, Paul J Coffer, Rienk Offringa, Mohamed R Daha, and Cees van Kooten Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands Department of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, The Netherlands Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands * Corresponding author; email: A.M.Woltman{at}lumc.nl. The longevity of dendritic cells (DCs) is a critical regulatory factor influencing the outcome of immune responses. Recently, we demonstrated that the immunosuppressive drug rapamycin (Rapa) specifically induces apoptosis in DCs, but not in other myeloid cell types. The present study unraveled the mechanism used by Rapa to induce apoptosis in human monocyte-derived DCs. Our data demonstrate that GM-CSF preserves DC survival specifically via the PI3K/mTOR signaling pathway, which is abrogated by Rapa at the level of mTOR. Disruption of this GM-CSF signaling pathway, induced loss of mitochondrial membrane potential, phosphatidyl-serine exposure and nuclear changes. Apoptosis of these non-proliferating DCs was preceded by an upregulation of the cell cycle inhibitor p27KIP1. Overexpression of p27KIP1 in DCs using adenoviral gene transduction revealed that apoptosis is directly regulated by p27KIP1. Furthermore, both overexpression of p27KIP1 and disruption of the GM-CSF/PI3K/mTOR signaling pathway decreased the expression of the anti-apoptotic protein mcl-1. This mTOR/p27KIP1/mcl-1 survival seems unique for DCs and may provide novel opportunities to influence immune responses by specific interference with the life-span of these cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. M. Janelsins, A. R. Mathers, O. A. Tkacheva, G. Erdos, W. J. Shufesky, A. E. Morelli, and A. T. Larregina Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity Blood, March 26, 2009; 113(13): 3017 - 3026. [Abstract] [Full Text] [PDF] T Weichhart and M D Saemann The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii70 - iii74. [Abstract] [Full Text] [PDF] W. Reichardt, C. Durr, D. von Elverfeldt, E. Juttner, U. V. Gerlach, M. Yamada, B. Smith, R. S. Negrin, and R. Zeiser Impact of Mammalian Target of Rapamycin Inhibition on Lymphoid Homing and Tolerogenic Function of Nanoparticle-Labeled Dendritic Cells following Allogeneic Hematopoietic Cell Transplantation J. Immunol., October 1, 2008; 181(7): 4770 - 4779. [Abstract] [Full Text] [PDF] H. R. Turnquist, T. L. Sumpter, A. Tsung, A. F. Zahorchak, A. Nakao, G. J. Nau, F. Y. Liew, D. A. Geller, and A. W. Thomson IL-1{beta}-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells J. Immunol., July 1, 2008; 181(1): 62 - 72. [Abstract] [Full Text] [PDF] R. T. Woodland, C. J. Fox, M. R. Schmidt, P. S. Hammerman, J. T. Opferman, S. J. Korsmeyer, D. M. Hilbert, and C. B. Thompson Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival Blood, January 15, 2008; 111(2): 750 - 760. [Abstract] [Full Text] [PDF] E. Kakazu, N. Kanno, Y. Ueno, and T. Shimosegawa Extracellular Branched-Chain Amino Acids, Especially Valine, Regulate Maturation and Function of Monocyte-Derived Dendritic Cells J. Immunol., November 15, 2007; 179(10): 7137 - 7146. [Abstract] [Full Text] [PDF] U. A. Hasan, C. Caux, I. Perrot, A.-C. Doffin, C. Menetrier-Caux, G. Trinchieri, M. Tommasino, and J. Vlach Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs PNAS, May 8, 2007; 104(19): 8047 - 8052. [Abstract] [Full Text] [PDF] C. Cutler, S. Li, V. T. Ho, J. Koreth, E. Alyea, R. J. Soiffer, and J. H. Antin Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation Blood, April 1, 2007; 109(7): 3108 - 3114. [Abstract] [Full Text] [PDF] E. Peponi, E. Drakos, G. Reyes, V. Leventaki, G. Z. Rassidakis, and L. J. Medeiros Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma Am. J. Pathol., December 1, 2006; 169(6): 2171 - 2180. [Abstract] [Full Text] [PDF] M. Utsugi, K. Dobashi, T. Ishizuka, T. Kawata, T. Hisada, Y. Shimizu, A. Ono, and M. Mori Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-{kappa}B p65 trans Activation Plays a Novel Role J. Immunol., October 1, 2006; 177(7): 4550 - 4557. [Abstract] [Full Text] [PDF] E. Kriehuber, W. Bauer, A.-S. Charbonnier, D. Winter, S. Amatschek, D. Tamandl, N. Schweifer, G. Stingl, and D. Maurer Balance between NF-{kappa}B and JNK/AP-1 activity controls dendritic cell life and death Blood, July 1, 2005; 106(1): 175 - 183. [Abstract] [Full Text] [PDF] E. Biecker, A. De Gottardi, M. Neef, M. Unternahrer, V. Schneider, M. Ledermann, H. Sagesser, S. Shaw, and J. Reichen Long-Term Treatment of Bile Duct-Ligated Rats with Rapamycin (Sirolimus) Significantly Attenuates Liver Fibrosis: Analysis of the Underlying Mechanisms J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 952 - 961. [Abstract] [Full Text] [PDF] T. J. Hagenbeek, M. Naspetti, F. Malergue, F. Garcon, J. A. Nunes, K. B.J.M. Cleutjens, J. Trapman, P. Krimpenfort, and H. Spits The Loss of PTEN Allows TCR {alpha}{beta} Lineage Thymocytes to Bypass IL-7 and Pre-TCR-mediated Signaling J. Exp. Med., October 4, 2004; 200(7): 883 - 894. [Abstract] [Full Text] [PDF] A. M. Woltman, N. Schlagwein, S. W. van der Kooij, and C. van Kooten The Novel Cyclophilin-Binding Drug Sanglifehrin A Specifically Affects Antigen Uptake Receptor Expression and Endocytic Capacity of Human Dendritic Cells J. Immunol., May 15, 2004; 172(10): 6482 - 6489. [Abstract] [Full Text] [PDF] S. L. Christian, R. L. Lee, S. J. McLeod, A. E. Burgess, A. H. Y. Li, M. Dang-Lawson, K. B. L. Lin, and M. R. Gold Activation of the Rap GTPases in B Lymphocytes Modulates B Cell Antigen Receptor-induced Activation of Akt but Has No Effect on MAPK Activation J. Biol. Chem., October 24, 2003; 278(43): 41756 - 41767. [Abstract] [Full Text] [PDF] J. H. Antin, H. T. Kim, C. Cutler, V. T. Ho, S. J. Lee, D. B. Miklos, E. P. Hochberg, C. J. Wu, E. P. Alyea, and R. J. Soiffer Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation Blood, September 1, 2003; 102(5): 1601 - 1605. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020