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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.
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Submitted January 5, 2005
Accepted April 29, 2005
Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn
Mark Lowenberg*, Jurriaan Tuynman, Joyce Bilderbeek, Timo Gaber, Frank Buttgereit, Sander van Deventer, Maikel Peppelenbosch, and Daniel Hommes
Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
Department of Rheumatology and Clinical Immunology, Charite University Hospital and Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Germany
Department of Cell Biology, University of Groningen, Groningen, The Netherlands
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
* Corresponding author; email: m.lowenberg{at}amc.uva.nl.
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. Employing 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 Lck/Fyn-consensus substrates. Immunoprecipitation and in vitro kinase assays reveal rapid GC-induced down modulation of Lck and Fyn kinases employing SAM68 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 PKB, PKC and MAPKs. Experiments with GC-receptor negative Jurkat cells and a pharmacological 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 hr in vivo. These results identify the inhibition of Lck and Fyn kinases as rapid targets of GCs, mediated via a GC-receptor dependent pathway.
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