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

Jenkins, BJ; Roberts, AW; Greenhill, CJ; Najdovska, M; Lundgren-May, T; Robb, L; Grail, D; Ernst, M

Author(s): Jenkins, BJ; Roberts, AW; Greenhill, CJ; Najdovska, M; Lundgren-May, T; Robb, L; Grail, D; Ernst, M;
Details: Publication Year 2007-03-15,Volume 109,Issue #6,Page 2380-2388
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: 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 9P130(Y757FN757F) mice lacking either IL-6 (9P130(Y757F1Y757F):1L-6(-/-)) or the IL-11 receptor a 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 9P130(Y757F/Y757F) mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor beta (TGF-beta) 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(Y717F1Y757F) mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6R alpha, and lL-6R alpha expression was reduced in 9P130(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.
Publisher: AMER SOC HEMATOLOGY
Keywords: GROWTH-FACTOR-BETA; LEUKEMIA INHIBITORY FACTOR; INTERLEUKIN-6 TRANSGENIC MICE; COLONY-STIMULATING FACTOR; RECEPTOR SUBUNIT GP130; IN-VIVO; MEGAKARYOCYTES INVITRO; SIGNAL TRANSDUCER; MUTANT MICE; ALPHA-CHAIN
Publisher's Version: https://doi.org/10.1182/blood-2006-08-040352
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Creation Date: 2007-03-15 12:00:00