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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 8, 2004 Accepted October 24, 2004 Nonsteroidal anti-inflammatory drugs inhibit a FYN dependent pathway coupled to RAC and stress kinase activation in TCR signaling Silvia R Paccani, Laura Patrussi, Cristina Ulivieri, Jaime L Masferrer, Mario M D'Elios, and Cosima T Baldari* Department of Evolutionary Biology, University of Siena, Siena, Italy Oncology Discovery Research, Pfizer Corporation, St. Louis, Missouri, USA Department of Internal Medicine and Immunoallergology, University of Florence, Florence, Italy * Corresponding author; email: baldari{at}unisi.it. In addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAID) harbour immunosuppressive activities, related to their capacity both to inhibit cyclooxygenases (COX) and to act as PPAR ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAID in T cells. Here we have investigated the effect of NSAID 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 NSAID also block activation of the stress kinase JNK, and that 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 NSAID inhibit the serine-threonine kinase Pak1 and the small GTPase Rac, as well as the Rac specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAID, while activation of Lck and of the Lck-dependent tyrosine kinase cascade is unaffacted. 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: V. A. Blaho, M. W. Buczynski, E. A. Dennis, and C. R. Brown Cyclooxygenase-1 Orchestrates Germinal Center Formation and Antibody Class-Switch via Regulation of IL-17 J. Immunol., November 1, 2009; 183(9): 5644 - 5653. [Abstract] [Full Text] [PDF] 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]

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