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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 29, 2004 Accepted December 26, 2004 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 Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia Division of Cancer and Hematology, The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia * Corresponding author; email: Brendan.Jenkins{at}ludwig.edu.au. 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 gp130 (gp130Y757F/Y757F) that leads to gp130-dependent STAT1/3 hyper-activation develop a broad spectrum of hematopoietic abnormalities, including splenomegaly, lymphadenopathy and thrombocytosis. To determine whether STAT3 hyper-activation 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 hyper-activation 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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