Abstract
To determine the importance of suppressor of cytokine signaling-3 (SOCS3) in the regulation of hematopoietic growth factor signaling generally, and of G-CSF-induced cellular responses specifically, we created mice in which the Socs3 gene was deleted in all hematopoietic cells. Although normal until young adulthood, these mice then developed neutrophilia and a spectrum of inflammatory pathologies. When stimulated with G-CSF in vitro, SOCS3-deficient cells of the neutrophilic granulocyte lineage exhibited prolonged STAT3 activation and enhanced cellular responses to G-CSF, including an increase in cloning frequency, survival, and proliferative capacity. Consistent with the in vitro findings, mutant mice injected with G-CSF displayed enhanced neutrophilia, progenitor cell mobilization, and splenomegaly, but unexpectedly also developed inflammatory neutrophil infiltration into multiple tissues and consequent hind-leg paresis. We conclude that SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells and that this is of particular significance during G-CSF-driven emergency granulopoiesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Granulocyte Colony-Stimulating Factor / immunology*
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Granulocyte Colony-Stimulating Factor / pharmacology
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Granulocytes / drug effects
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Granulocytes / immunology*
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Granulocytes / metabolism
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Hematopoiesis / physiology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / metabolism
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Inflammation / immunology
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Inflammation / pathology*
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Mice
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Mice, Transgenic
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / metabolism
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Repressor Proteins / immunology*
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STAT3 Transcription Factor
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / drug effects
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Trans-Activators / immunology
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Trans-Activators / metabolism
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Transcription Factors / deficiency
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Transcription Factors / immunology*
Substances
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DNA-Binding Proteins
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Repressor Proteins
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Granulocyte Colony-Stimulating Factor