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

BA Croker, D Metcalf, L Robb, W Wei, S Mifsud… - Immunity, 2004 - cell.com
BA Croker, D Metcalf, L Robb, W Wei, S Mifsud, L DiRago, LA Cluse, KD Sutherland…
Immunity, 2004cell.com
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 …
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.
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