SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis

Immunity. 2004 Feb;20(2):153-65. doi: 10.1016/s1074-7613(04)00022-6.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Granulocyte Colony-Stimulating Factor / immunology*
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Granulocytes / drug effects
  • Granulocytes / immunology*
  • Granulocytes / metabolism
  • Hematopoiesis / physiology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism
  • Inflammation / immunology
  • Inflammation / pathology*
  • Mice
  • Mice, Transgenic
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Repressor Proteins / immunology*
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / drug effects
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / immunology*


  • DNA-Binding Proteins
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Granulocyte Colony-Stimulating Factor