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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4841-4848. Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2005-10-4044. This Article Full Text (PDF) All Versions of this Article: 2005-10-4044v1 107/12/4841    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 Hermann-Kleiter, N. Articles by Baier, G. Search for Related Content PubMed PubMed Citation Articles by Hermann-Kleiter, N. Articles by Baier, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 19, 2005 Accepted February 10, 2006 PKC and PKA are antagonistic partners in the NF-AT transactivation pathway of primary mouse CD3+ T lymphocytes Natascha Hermann-Kleiter, Nikolaus Thuille, Christa Pfeifhofer, Thomas Gruber, Michaela Schafer, Christof Zitt, Armin Hatzelmann, Christian Schudt, Michael Leitges, and Gottfried Baier* Department for Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria Altana Pharma AG, Konstanz, Germany Medical University, Hanover, Germany * Corresponding author; email: gottfried.baier{at}i-med.ac.at. We here investigate the crosstalk of PKC and PKA signalling during primary CD3+ T lymphocyte activation using pharmacological inhibitors and activators in combination with our established panel of PKC isotype-deficient mouse T cells in vitro. PKC and PKA inversely affect the CD3/CD28-induced IL-2 expression, whereas other PKC isotypes are dispensable in this signalling pathway. Gene ablation of PKC selectively results in a profound reduction of IL-2 production, however, complete abrogation of IL-2 production in these PKC-/- T cells was only achieved by simultaneous co-activation of the cAMP/PKA pathway in CD3+ T cells. Conversely, the reduced IL-2 production in PKC inhibitor treated T cells can be rescued by inhibition of the cAMP/PKA pathway in wild-type but not in PKC-/- T cells. Mechanistically, the cAMP/PKA and PKC pathways converge at the level of NF-AT, as shown by DNA binding analysis. The combined increase in PKA and decrease in PKCtheta activity leads to an enhanced inhibition of nuclear NF-AT translocation. This PKC/PKA crosstalk does neither significantly affect the NF-B, the AP-1 nor the CREB pathways. Taken together, this opposite effect between the positive PKC and the negative cAMP/PKA signalling pathways appears rate limiting for NF-AT transactivation and IL-2 secretion responses of CD3+ T lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-P. Evenou, J. Wagner, G. Zenke, V. Brinkmann, K. Wagner, J. Kovarik, K. A. Welzenbach, G. Weitz-Schmidt, C. Guntermann, H. Towbin, et al. The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 792 - 801. [Abstract] [Full Text] [PDF] T. Gruber, N. Hermann-Kleiter, R. Hinterleitner, F. Fresser, R. Schneider, G. Gastl, J. M. Penninger, and G. Baier PKC-{theta} Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation Sci. Signal., June 23, 2009; 2(76): ra30 - ra30. [Abstract] [Full Text] [PDF] A. Norambuena, C. Metz, L. Vicuna, A. Silva, E. Pardo, C. Oyanadel, L. Massardo, A. Gonzalez, and A. Soza Galectin-8 Induces Apoptosis in Jurkat T Cells by Phosphatidic Acid-mediated ERK1/2 Activation Supported by Protein Kinase A Down-regulation J. Biol. Chem., May 8, 2009; 284(19): 12670 - 12679. [Abstract] [Full Text] [PDF] T. Letschka, V. Kollmann, C. Pfeifhofer-Obermair, C. Lutz-Nicoladoni, G. J. Obermair, F. Fresser, M. Leitges, N. Hermann-Kleiter, S. Kaminski, and G. Baier PKC-{theta} selectively controls the adhesion-stimulating molecule Rap1 Blood, December 1, 2008; 112(12): 4617 - 4627. [Abstract] [Full Text] [PDF] T. Bopp, C. Becker, M. Klein, S. Klein-Hessling, A. Palmetshofer, E. Serfling, V. Heib, M. Becker, J. Kubach, S. Schmitt, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell mediated suppression J. Exp. Med., June 11, 2007; 204(6): 1303 - 1310. [Abstract] [Full Text] [PDF]

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