The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis.
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(Y757F/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.
Jenkins
Brendan J
BJ
Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory, PO Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia. brendan.jenkins@ludwig.edu.au
Roberts
Andrew W
AW
Najdovska
Meri
M
Grail
Dianne
D
Ernst
Matthias
M
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000502:physiology*; D005838:Genotype; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D013163:Splenomegaly / Q000235:genetics; D013922:Thrombocytosis / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130