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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3512-3520. Prepublished online as a Blood First Edition Paper on January 13, 2005; DOI 10.1182/blood-2004-09-3751. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2004-09-3751v1 105/9/3512    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 Jenkins, B. J. Articles by Ernst, M. Search for Related Content PubMed PubMed Citation Articles by Jenkins, B. J. Articles by Ernst, M. Related Collections Hematopoiesis and Stem Cells Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis Brendan J. Jenkins, Andrew W. Roberts, Meri Najdovska, Dianne Grail, and Matthias Ernst From the Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory; and Division of Cancer and Haematology, The Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Parkville, Victoria, Australia. The interleukin-6 (IL-6) cytokine family plays an important role in regulating cellular responses during hematopoiesis. We report here that mice homozygous for a knock-in mutation in the IL-6 cytokine family receptor signaling subunit glycoprotein (gp) 130 (gp130Y757F/Y757F) that leads to gp130-dependent signal transducers and activators of transcription (STAT) 1/3 hyperactivation develop a broad spectrum of hematopoietic abnormalities, including splenomegaly, lymphadenopathy, and thrombocytosis. To determine whether STAT3 hyperactivation was responsible for the perturbed hematopoiesis in gp130Y757F/Y757F mice, we generated gp130Y757F/Y757F mice on a Stat3 heterozygous (Stat3+/-) background to specifically reduce gp130-dependent activation of STAT3, but not STAT1. Normal hematopoiesis was observed in gp130Y757F/Y757F:Stat3+/- bone marrow and spleen, with no evidence of the splenomegaly and thrombocytosis displayed by gp130Y757F/Y757F mice. The perturbed cellular composition of thymus and lymph nodes in gp130Y757F/Y757F mice was also alleviated in gp130Y757F/Y757F: Stat3+/- mice. Furthermore, we show that hematopoietic cells from gp130Y757F/Y757F mice exhibited increased survival and proliferation in response to IL-6 family cytokines. Collectively, these data provide genetic evidence that gp130-dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs, and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K.-H. Chuang, S. Altuwaijri, G. Li, J.-J. Lai, C.-Y. Chu, K.-P. Lai, H.-Y. Lin, J.-W. Hsu, P. Keng, M.-C. Wu, et al. Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor J. Exp. Med., May 11, 2009; 206(5): 1181 - 1199. [Abstract] [Full Text] [PDF] C. A. Fielding, R. M. McLoughlin, L. McLeod, C. S. Colmont, M. Najdovska, D. Grail, M. Ernst, S. A. Jones, N. Topley, and B. J. Jenkins IL-6 Regulates Neutrophil Trafficking during Acute Inflammation via STAT3 J. Immunol., August 1, 2008; 181(3): 2189 - 2195. [Abstract] [Full Text] [PDF] M. S. Redell, A. Tsimelzon, S. G. Hilsenbeck, and D. J. Tweardy Conditional overexpression of Stat3{alpha} in differentiating myeloid cells results in neutrophil expansion and induces a distinct, antiapoptotic and pro-oncogenic gene expression pattern J. Leukoc. Biol., October 1, 2007; 82(4): 975 - 985. [Abstract] [Full Text] [PDF] C. Brender, G. M. Tannahill, B. J. Jenkins, J. Fletcher, R. Columbus, C. J. M. Saris, M. Ernst, N. A. Nicola, D. J. Hilton, W. S. Alexander, et al. Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27 Blood, October 1, 2007; 110(7): 2528 - 2536. [Abstract] [Full Text] [PDF] D. Wang, Z. Liu, Q. Li, M. Karpurapu, V. Kundumani-Sridharan, H. Cao, N. Dronadula, F. Rizvi, A. K. Bajpai, C. Zhang, et al. An Essential Role for gp130 in Neointima Formation Following Arterial Injury Circ. Res., March 30, 2007; 100(6): 807 - 816. [Abstract] [Full Text] [PDF] B. J. Jenkins, A. W. Roberts, C. J. Greenhill, M. Najdovska, T. Lundgren-May, L. Robb, D. Grail, and M. Ernst Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis Blood, March 15, 2007; 109(6): 2380 - 2388. [Abstract] [Full Text] [PDF] C. A. Fielding, R. M. McLoughlin, C. S. Colmont, M. Kovaleva, D. A. Harris, S. Rose-John, N. Topley, and S. A. Jones Viral IL-6 Blocks Neutrophil Infiltration during Acute Inflammation J. Immunol., September 15, 2005; 175(6): 4024 - 4029. [Abstract] [Full Text] [PDF] R. M. McLoughlin, B. J. Jenkins, D. Grail, A. S. Williams, C. A. Fielding, C. R. Parker, M. Ernst, N. Topley, and S. A. Jones IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation PNAS, July 5, 2005; 102(27): 9589 - 9594. [Abstract] [Full Text] [PDF]

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