SOCS3 Is a Critical Physiological Negative Regulator of G-CSF Signaling and Emergency Granulopoiesis

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.

General Nature of the STAT3-Activated Anti-Inflammatory Response

“…Mice with point mutations in S727 of STAT3 and Y757 of gp130 have been described in detail (15,16). The suppressor of cytokine signaling (SOCS) gene in Socs3 Ϫ/fl ; lysMcre or Socs3 ϩ/fl ; lysMcre mice have been described previously (17). Socs3 fl/fl ; lysMcre mice were bred at St. Jude Children's Research Hospital and used as a source of macrophages for the remaining experiments.…”

Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors

“…30 All cells were cultured in 0.3% agar in Dulbecco modified Eagle medium (DMEM) containing 20% FCS. Cytokines were used at the final concentrations of 10 ng/mL murine IL-3, 100 ng/mL murine SF, 2 U/mL rhEpo, and 10 ng/mL murine granulocyte macrophage (GM)-CSF.…”

Knocking Off SOCS Genes in the Mammary Gland

“…[19][20][21] In myeloid cells, Socs3 has been demonstrated to be an important attenuator of signaling by granulocyte colony-stimulating factor (G-CSF). 22,23 Within mammary epithelium, Socs3 expression is induced to varying magnitudes by PRL and EGF, with the highest induction occurring in response to EGF stimulation in both the mammary gland and HC11 mouse epithelial cells. 24 Expression profiling analyses of the different stages of mammary gland involution showed that Socs3 was highly upregulated during the first four days of this phase.…”