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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4135-4142. Prepublished online as a Blood First Edition Paper on January 18, 2007; DOI 10.1182/blood-2006-10-054973. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-054973v1 109/10/4135    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 Zeng, R. Articles by Leonard, W. J. Search for Related Content PubMed PubMed Citation Articles by Zeng, R. Articles by Leonard, W. J. Related Collections Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS The molecular basis of IL-21–mediated proliferation Rong Zeng1, Rosanne Spolski1, Esther Casas2, Wei Zhu2, David E. Levy2, and Warren J. Leonard1 1 Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD; 2 Departments of Pathology and Microbiology, New York University (NYU) School of Medicine, New York, NY Interleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells. The IL-21 receptor (IL-21R) is closely related to the IL-2 receptor ß chain and is capable of transducing signals through its dimerization with the common cytokine receptor chain (c), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency. To clarify the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain. Simultaneous mutation of all 6 tyrosines greatly diminished IL-21–mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation. Y510 efficiently mediated IL-21–induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8+ T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15. In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21–mediated proliferation. Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Mizuguchi, H. Asao, T. Hara, M. Higuchi, M. Fujii, and M. Nakamura Transcriptional Activation of the Interleukin-21 Gene and Its Receptor Gene by Human T-cell Leukemia Virus Type 1 Tax in Human T-cells J. Biol. Chem., September 18, 2009; 284(38): 25501 - 25511. [Abstract] [Full Text] [PDF] 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] R. Spolski, H.-P. Kim, W. Zhu, D. E. Levy, and W. J. Leonard IL-21 Mediates Suppressive Effects via Its Induction of IL-10 J. Immunol., March 1, 2009; 182(5): 2859 - 2867. [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] M. Huber, A. Brustle, K. Reinhard, A. Guralnik, G. Walter, A. Mahiny, E. von Low, and M. Lohoff IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype PNAS, December 30, 2008; 105(52): 20846 - 20851. [Abstract] [Full Text] [PDF] K. Castermans, S. P. Tabruyn, R. Zeng, J. R. van Beijnum, C. Eppolito, W. J. Leonard, P. A. Shrikant, and A. W. Griffioen Angiostatic activity of the antitumor cytokine interleukin-21 Blood, December 15, 2008; 112(13): 4940 - 4947. [Abstract] [Full Text] [PDF] E. Menoret, S. Maiga, G. Descamps, C. Pellat-Deceunynck, C. Fraslon, M. Cappellano, P. Moreau, R. Bataille, and M. Amiot IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop J. Immunol., November 15, 2008; 181(10): 6837 - 6842. [Abstract] [Full Text] [PDF] W. J. Leonard, R. Zeng, and R. Spolski Interleukin 21: a cytokine/cytokine receptor system that has come of age J. Leukoc. Biol., August 1, 2008; 84(2): 348 - 356. [Abstract] [Full Text] [PDF] J. Gagnon, S. Ramanathan, C. Leblanc, A. Cloutier, P. P. McDonald, and S. Ilangumaran IL-6, in Synergy with IL-7 or IL-15, Stimulates TCR-Independent Proliferation and Functional Differentiation of CD8+ T Lymphocytes J. Immunol., June 15, 2008; 180(12): 7958 - 7968. [Abstract] [Full Text] [PDF] C. S. Hinrichs, R. Spolski, C. M. Paulos, L. Gattinoni, K. W. Kerstann, D. C. Palmer, C. A. Klebanoff, S. A. Rosenberg, W. J. Leonard, and N. P. Restifo IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy Blood, June 1, 2008; 111(11): 5326 - 5333. [Abstract] [Full Text] [PDF] S. A. Diehl, H. Schmidlin, M. Nagasawa, S. D. van Haren, M. J. Kwakkenbos, E. Yasuda, T. Beaumont, F. A. Scheeren, and H. Spits STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation J. Immunol., April 1, 2008; 180(7): 4805 - 4815. [Abstract] [Full Text] [PDF] M. Marzec, K. Halasa, M. Kasprzycka, M. Wysocka, X. Liu, J. W. Tobias, D. Baldwin, Q. Zhang, N. Odum, A. H. Rook, et al. Differential Effects of Interleukin-2 and Interleukin-15 versus Interleukin-21 on CD4+ Cutaneous T-Cell Lymphoma Cells Cancer Res., February 15, 2008; 68(4): 1083 - 1091. [Abstract] [Full Text] [PDF] F. Caprioli, M. Sarra, R. Caruso, C. Stolfi, D. Fina, G. Sica, T. T. MacDonald, F. Pallone, and G. Monteleone Autocrine Regulation of IL-21 Production in Human T Lymphocytes J. Immunol., February 1, 2008; 180(3): 1800 - 1807. [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] L. Wei, A. Laurence, K. M. Elias, and J. J. O'Shea IL-21 Is Produced by Th17 Cells and Drives IL-17 Production in a STAT3-dependent Manner J. Biol. Chem., November 30, 2007; 282(48): 34605 - 34610. [Abstract] [Full Text] [PDF] S. Liu, G. Lizee, Y. Lou, C. Liu, W. W. Overwijk, G. Wang, and P. Hwu IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells Int. Immunol., October 1, 2007; 19(10): 1213 - 1221. [Abstract] [Full Text] [PDF] B. R. Barker, J. G. Parvani, D. Meyer, A. S. Hey, K. Skak, and N. L. Letvin IL-21 Induces Apoptosis of Antigen-Specific CD8+ T Lymphocytes J. Immunol., September 15, 2007; 179(6): 3596 - 3603. [Abstract] [Full Text] [PDF] G. Cassese, E. Parretta, L. Pisapia, A. Santoni, J. Guardiola, and F. Di Rosa Bone marrow CD8 cells down-modulate membrane IL-7R{alpha} expression and exhibit increased STAT-5 and p38 MAPK phosphorylation in the organ environment. Blood, September 15, 2007; 110(6): 1960 - 1969. [Abstract] [Full Text] [PDF] V. Ostiguy, E.-L. Allard, M. Marquis, J. Leignadier, and N. Labrecque IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade J. Leukoc. Biol., September 1, 2007; 82(3): 645 - 656. [Abstract] [Full Text] [PDF]

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