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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.

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HEMATOPOIESIS

Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis

Brendan J. Jenkins1,2, Andrew W. Roberts3, Claire J. Greenhill2, Meri Najdovska2, Therese Lundgren-May1, Lorraine Robb3, Dianne Grail1, and Matthias Ernst1

1 Ludwig Institute for Cancer Research, Victoria, Australia; 2 Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; 3 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

We have previously demonstrated that STAT3 hyperactivation via the interleukin 6 (IL-6) cytokine family receptor gp130 in gp130 Y757F/Y757F mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Because 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 gp130 Y757F/Y757F mice lacking either IL-6 (gp130 Y757F/Y757F: IL-6 –/–) or the IL-11 receptor {alpha} subunit (gp130 Y757F/Y757F: IL-11R{alpha}1 –/–), and this was associated with a normalized bone marrow compartment. The elevated myelopoiesis and megakaryopoiesis in bone marrow of gp130 Y757F/Y757F mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor ß (TGF-ß) signaling, which is a suppressor of these lineages. In contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130 Y757F/Y757F mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6R{alpha}, and IL-6R{alpha} expression was reduced in gp130 Y757F/Y757F: Stat3 +/– mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathologic hematopoietic and lymphoid responses mediated by STAT3 hyperactivation.


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