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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1703-1710. Prepublished online as a Blood First Edition Paper on May 17, 2005; DOI 10.1182/blood-2004-12-4790. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 2004-12-4790v1 106/5/1703    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Löwenberg, M. Articles by Hommes, D. Search for Related Content PubMed PubMed Citation Articles by Löwenberg, M. Articles by Hommes, D. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn Mark Löwenberg, Jurriaan Tuynman, Joyce Bilderbeek, Timo Gaber, Frank Buttgereit, Sander van Deventer, Maikel Peppelenbosch, and Daniel Hommes From the Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands; the Department of Rheumatology and Clinical Immunology (Charité University Hospital) and Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Germany; the Department of Cell Biology, University of Groningen, Groningen, The Netherlands; and the Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. Glucocorticoids (GCs) are effective immunosuppressive agents and mediate well-defined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4+ lymphocytes and a peptide array containing 1176 different kinase consensus substrates, we generated a comprehensive profile of GC-induced rapid effects on signal transduction. The results show marked early differences in phosphorylation between GC-pretreated cells and control cells, including impaired phosphorylation of p56lck/p59fyn (Lck/Fyn) consensus substrates. Immunoprecipitation and in vitro kinase assays reveal rapid GC-induced down-modulation of Lck and Fyn kinases using SAM68 (Src [pp60c-src]-associated in mitosis 68 kDa) as a substrate. Additionally, immunoprecipitation experiments revealed reduced Lck-CD4 and Fyn-CD3 associations, suggesting GC inhibited recruitment of these kinases to the T-cell receptor complex. Western blot analysis revealed reduced phosphorylation of a series of downstream signaling intermediates following GC treatment, including protein kinase B (PKB), protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Experiments with GC receptor-negative Jurkat cells and a pharmacologic GC receptor ligand (RU486) indicated that rapid inhibition of Lck and Fyn kinases is GC receptor dependent. Parallel experiments conducted following the application of GCs in healthy individuals confirmed suppression of Lck/Fyn in T cells within 1 hour in vivo. These results identify the inhibition of Lck and Fyn kinases as rapid targets of GCs, mediated via a GC receptor-dependent pathway. (Blood. 2005; 106:1703-1710) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. B. Tuynman, L. Vermeulen, E. M. Boon, K. Kemper, A. H. Zwinderman, M. P. Peppelenbosch, and D. J. Richel Cyclooxygenase-2 Inhibition Inhibits c-Met Kinase Activity and Wnt Activity in Colon Cancer Cancer Res., February 15, 2008; 68(4): 1213 - 1220. [Abstract] [Full Text] [PDF] M. Perretti Glucocorticoids in innate immunity: more transactivation than transrepression! Blood, February 1, 2007; 109(3): 852 - 853. [Full Text] [PDF] M. Zeyda, R. Geyeregger, M. Poglitsch, T. Weichhart, G. J. Zlabinger, S. Koyasu, W. H. Horl, T. M. Stulnig, B. Watschinger, and M. D. Saemann Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-{kappa}B in immunological synapse formation J. Leukoc. Biol., January 1, 2007; 81(1): 319 - 327. [Abstract] [Full Text] [PDF] J. W.P.M. van Baal, S. H. Diks, R. J.A. Wanders, A. M. Rygiel, F. Milano, J. Joore, J. J.G.H.M. Bergman, M. P. Peppelenbosch, and K. K. Krishnadath Comparison of Kinome Profiles of Barrett's Esophagus with Normal Squamous Esophagus and Normal Gastric Cardia Cancer Res., December 15, 2006; 66(24): 11605 - 11612. [Abstract] [Full Text] [PDF] M. Lowenberg, J. Tuynman, M. Scheffer, A. Verhaar, L. Vermeulen, S. van Deventer, D. Hommes, and M. Peppelenbosch Kinome Analysis Reveals Nongenomic Glucocorticoid Receptor-Dependent Inhibition of Insulin Signaling Endocrinology, July 1, 2006; 147(7): 3555 - 3562. [Abstract] [Full Text] [PDF]

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