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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4351-4359. Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-09-047563. This Article Full Text (PDF) All Versions of this Article: blood-2006-09-047563v1 109/10/4351    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 Adler, H. S. Articles by Steinbrink, K. Search for Related Content PubMed PubMed Citation Articles by Adler, H. S. Articles by Steinbrink, K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 18, 2006 Accepted January 12, 2007 Activation of MAP kinase p38 is critical for the cell cycle controlled suppressor function of regulatory T cells Henric S. Adler, Sebastian Kubsch, Edith Graulich, Stephan Ludwig, Juergen Knop, and Kerstin Steinbrink* Dept of Dermatology, University of Mainz, Germany Institute of Molecular Virology, University of Muenster, Germany * Corresponding author; email: steinbrink{at}hautklinik.klinik.uni-mainz.de. Regulatory T cells play an essential role in the control of self tolerance and processes of adaptive immunity. Tolerogenic IL-10-modulated human dendritic cells (IL-10DCs) induce anergic T cells with strong suppressive properties (iTregs) that inhibit the activation of effector T cells. In this study, we evaluated the interaction between cell cycle regulation and intracellular signaling in these iTregs. Analysis of signal transduction events revealed a downregulation of the mitogen-activated protein kinases (MAPKs) JNK and a non-activation of ERK in contrast to a marked activation of p38 MAPK and the p38 effector MAPK-activated protein kinases 2/3 (MAPKAP2/3). The elevated activation of p38 is critical for the induction and maintenance of anergy controlled by an increased expression of the cell cycle inhibitor p27Kip1. Moreover, blocking experiments with the specific inhibitor SB203580 demonstrated that the regulatory function of iTregs is associated with an enhanced p38 MAP kinase activity. In contrast to other Treg populations, the suppressor function of iTregs is independent of IL-10. In conclusion, our data indicate that a cross talk of cell cycle regulation and p38 dependent signal transduction is required for the suppressor function of iTregs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Yessoufou, A. Ple, K. Moutairou, A. Hichami, and N. A. Khan Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells J. Lipid Res., December 1, 2009; 50(12): 2377 - 2388. [Abstract] [Full Text] [PDF] L. Gabrysova, K. S. Nicolson, H. B. Streeter, J. Verhagen, C. A. Sabatos-Peyton, D. J. Morgan, and D. C. Wraith Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells J. Exp. Med., August 3, 2009; 206(8): 1755 - 1767. [Abstract] [Full Text] [PDF] F. Zhao, C. Falk, W. Osen, M. Kato, D. Schadendorf, and V. Umansky Activation of p38 Mitogen-Activated Protein Kinase Drives Dendritic Cells to Become Tolerogenic in Ret Transgenic Mice Spontaneously Developing Melanoma Clin. Cancer Res., July 1, 2009; 15(13): 4382 - 4390. [Abstract] [Full Text] [PDF] E. V. Lourenco, C. Procaccini, F. Ferrera, N. Iikuni, R. P. Singh, G. Filaci, G. Matarese, F.-D. Shi, E. Brahn, B. H. Hahn, et al. Modulation of p38 MAPK Activity in Regulatory T Cells after Tolerance with Anti-DNA Ig Peptide in (NZB x NZW)F1 Lupus Mice J. Immunol., June 15, 2009; 182(12): 7415 - 7421. [Abstract] [Full Text] [PDF]

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