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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3708-3715. Prepublished online as a Blood First Edition Paper on January 3, 2006; DOI 10.1182/blood-2005-09-3535. This Article Full Text (PDF) All Versions of this Article: 2005-09-3535v1 107/9/3708    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 de Totero, D. Articles by Ferrini, S. Search for Related Content PubMed PubMed Citation Articles by de Totero, D. Articles by Ferrini, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 1, 2005 Accepted December 27, 2005 Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates pro-apoptotic signals in chronic lymphocytic leukemia B cells Daniela de Totero, Raffaella Meazza, Simona Zupo, Giovanna Cutrona, Serena Matis, Monica Colombo, Enrico Balleari, Ivana Pierri, Marina Fabbi, Matteo Capaia, Bruno Azzarone, Marco Gobbi, Manlio Ferrarini, and Silvano Ferrini* Dept. of Translational Oncology and Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy Clinical and Experimental Immunology, Istituto G. Gaslini, Genoa, Italy Dept. of Hematology and Oncology, University of Genoa, Genoa, Italy Hematology and Oncology, University of Genoa, Genoa, Italy * Corresponding author; email: silvano.ferrini{at}istge.it. IL-21 is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21R is expressed at variable levels by CLL B cells freshly isolated from 33 different patients. IL-21R expression was up-regulated following cell stimulation via surface CD40. Therefore IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signalling cascade in CLL B cells, which included Jak-1 and 3 auto-phosphorylation and tyrosine phosphorylation of STAT-1, -3 and 5. IL-21 signalling failed to stimulate CLL B cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and anti-apoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and 3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27/Kip-1. Recent data indicate that CLL B cells require interaction with the micoenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Dien Bard, P. Gelebart, M. Anand, Z. Zak, S. A. Hegazy, H. M. Amin, and R. Lai IL-21 Contributes to JAK3/STAT3 Activation and Promotes Cell Growth in ALK-Positive Anaplastic Large Cell Lymphoma Am. J. Pathol., August 1, 2009; 175(2): 825 - 834. [Abstract] [Full Text] [PDF] D. Konforte, N. Simard, and C. J. Paige IL-21: An Executor of B Cell Fate J. Immunol., February 15, 2009; 182(4): 1781 - 1787. [Abstract] [Full Text] [PDF] B. Lamprecht, S. Kreher, I. Anagnostopoulos, K. Johrens, G. Monteleone, F. Jundt, H. Stein, M. Janz, B. Dorken, and S. 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Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways Blood, January 15, 2008; 111(2): 517 - 524. [Abstract] [Full Text] [PDF] I. D. Davis, K. Skak, M. J. Smyth, P. E.G. Kristjansen, D. M. Miller, and P. V. Sivakumar Interleukin-21 Signaling: Functions in Cancer and Autoimmunity Clin. Cancer Res., December 1, 2007; 13(23): 6926 - 6932. [Abstract] [Full Text] [PDF] A. P. Kater, M. H. J. van Oers, and T. J. Kipps Cellular immune therapy for chronic lymphocytic leukemia Blood, October 15, 2007; 110(8): 2811 - 2818. [Abstract] [Full Text] [PDF] D. Konforte and C. J. Paige Identification of Cellular Intermediates and Molecular Pathways Induced by IL-21 in Human B Cells J. Immunol., December 15, 2006; 177(12): 8381 - 8392. [Abstract] [Full Text] [PDF] K. L. Good, V. L. Bryant, and S. G. 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