SEARCH:   Advanced

Blood, 1 March 2005, Vol. 105, No. 5, pp. 2042-2048. Prepublished online as a Blood First Edition Paper on October 28, 2004; DOI 10.1182/blood-2004-04-1299. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2004-04-1299v1 105/5/2042    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 Paccani, S. R. Articles by Baldari, C. T. Search for Related Content PubMed PubMed Citation Articles by Paccani, S. R. Articles by Baldari, C. T. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling Silvia Rossi Paccani, Laura Patrussi, Cristina Ulivieri, Jaime L. Masferrer, Mario Milco D'Elios, and Cosima T. Baldari From the Department of Evolutionary Biology, University of Siena, Siena, Italy; Oncology Discovery Research, Pfizer Corporation, St Louis, MO; and Department of Internal Medicine and Immunoallergology, University of Florence, Florence, Italy. In addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) harbor immunosuppressive activities related to their capacity both to inhibit cyclooxygenases (COXs) and to act as peroxisome proliferator-activated receptor (PPAR) ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAIDs in T cells. Here we have investigated the effect of NSAIDs on the signaling pathway triggered by the T-cell antigen receptor (TCR) and leading to stress kinase activation. The results show that nonselective and COX-1–selective NSAIDs also block activation of the stress kinase c-Jun N-terminal kinase (JNK) and that prostaglandin-E2 (PGE2) reverses this block and enhances TCR-dependent JNK activation. Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5'-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAIDs, whereas activation of lymphocyte-specific protein tyrosine kinase (Lck) and of the Lck-dependent tyrosine kinase cascade is unaffected. Accordingly, constitutively active Fyn reverses the NSAID-dependent stress kinase inhibition. The data identify COX-1 as an important early modulator of TCR signaling and highlight a TCR proximal pathway selectively coupling the TCR to stress kinase activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Patrussi, C. Ulivieri, O. M. Lucherini, S. R. Paccani, A. Gamberucci, L. Lanfrancone, P. G. Pelicci, and C. T. Baldari p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells Blood, September 15, 2007; 110(6): 1730 - 1738. [Abstract] [Full Text] [PDF] O. Gasser, T. A. Schmid, G. Zenhaeusern, and C. Hess Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells J. Immunol., December 15, 2006; 177(12): 8806 - 8812. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020