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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2380-2388. Prepublished online as a Blood First Edition Paper on November 2, 2006; DOI 10.1182/blood-2006-08-040352. This Article Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2006-08-040352v1 109/6/2380    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 August 14, 2006 Accepted October 25, 2006 Pathological consequences of STAT3 hyper-activation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis Brendan J Jenkins*, Andrew W Roberts, Claire J Greenhill, Meri Najdovska, Therese Lundgren-May, Lorraine Robb, Dianne Grail, and Matthias Ernst Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia Walter and Eliza Hall Institute of Medical Research, Victoria, Australia Centre for Functional Genomics & Human Disease, Monash Institute of Medical Research, Monash University, Victoria, Australia * Corresponding author; email: brendan.jenkins{at}med.monash.edu.au. We have previously demonstrated that STAT3 hyper-activation via the interleukin (IL)-6 cytokine family receptor gp130 in gp130Y757F/Y757F mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Since IL-6 and IL-11 both signal via a gp130 homodimer, we report here a genetic approach to dissect their individual roles in these pathologies. Neutrophilia and thrombocytosis were absent in gp130Y757F/Y757F mice lacking either IL-6 (gp130Y757F/Y757F:IL-6-/-) or the IL-11 receptor subunit (gp130Y757F/Y757F:IL-11R1-/-), and this was associated with a normalized bone marrow compartment. The elevated myelo- and megakaryopoiesis in bone marrow of gp130Y757F/Y757F mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor (TGF) signaling, which is a suppressor of these lineages. In contrast, the absence of IL-6, but not IL-11 signaling, corrected the splenomegaly, abnormal lymphopoiesis and STAT3 hyper-activation in lymphoid organs of gp130Y757F/Y757F mice. Furthermore, hyper-activation of STAT3 in lymphoid organs was associated with increased expression of IL-6R, and IL-6R expression was reduced in gp130Y757F/Y757F:Stat3-/+ mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathological hematopoietic and lymphoid responses mediated by STAT3 hyper-activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. Senyuk, C. R. Rinaldi, D. Li, F. Cattaneo, A. Stojanovic, F. Pane, X. Du, N. Mahmud, J. Dickstein, and G. Nucifora Consistent Up-regulation of Stat3 Independently of Jak2 Mutations in a New Murine Model of Essential Thrombocythemia Cancer Res., January 1, 2009; 69(1): 262 - 271. [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] F. Li, Y. S. Devi, L. Bao, J. Mao, and G. Gibori Involvement of Cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) in Interleukin 11 Stimulation of Decidualization in Mice Biol Reprod, January 1, 2008; 78(1): 127 - 133. [Abstract] [Full Text] [PDF]

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