The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis

Jenkins, BJ; Roberts, AW; Najdovska, M; Grail, D; Ernst, M

Author(s): Jenkins, BJ; Roberts, AW; Najdovska, M; Grail, D; Ernst, M;
Details: Publication Year 2005-05-01,Volume 105,Issue #9,Page 3512-3520
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: 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 (gp130(Y757F/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 gp130(Y757F/Y757F) mice, we generated gp130(Y757F/Y757F) mice on a Stat3 heterozygous (Stat3(+/-)) background to specifically reduce gp130-dependent activation of STAT3, but not STAT1. Normal hematopoiesis was observed in gp130(Y757F/Y757F):Stat3(+/-) bone marrow and spleen, with no evidence of the splenomegaly and thrombocytosis displayed by gp130(Y757F/Y757F) mice. The perturbed cellular composition of thymus and lymph nodes in gp130(Y757F/Y757F) mice was also alleviated in gp130(Y717F/Y757F): Stat3(+/-) mice. Furthermore, we show that hematopoietic cells from gp130(Y757F/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. (c) 2005 by The American Society of Hematology.
Publisher: AMER SOC HEMATOLOGY
Keywords: LEUKEMIA INHIBITORY FACTOR; CYTOKINE RECEPTOR GP130; STEM-CELLS; TARGETED DISRUPTION; IN-VIVO; INTERLEUKIN-6 RECEPTOR; TRANSGENIC MICE; ACTIVATION; TRANSDUCER; EXPRESSION
Publisher's Version: https://doi.org/10.1182/blood-2004-09-3751
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2005-05-01 12:00:00