title: Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation.
abstract: Granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) play key roles in regulating emergency granulopoiesis and inflammation, and are both negatively regulated by the inducible intracellular protein suppressor of cytokine signaling-3 (Socs3). Mice with Socs3 deleted specifically in hematopoietic cells succumb to severe neutrophil and macrophage-driven inflammation by 1 year of age, and responses to G-CSF are grossly exacerbated. In order to determine which elements of cellular responses to cytokines require Socs3, we have examined the differentiative and proliferative capacity of hematopoietic progenitor cells stimulated by G-CSF and IL-6. The differentiation of Socs3-deficient progenitor cells is skewed toward macrophage production in response to G-CSF or IL-6, whereas wild-type progenitor cells produce mainly neutrophils. The proliferative capacity of Socs3-deficient progenitor cells is greatly enhanced in response to G-CSF at all concentrations, but only at low concentrations for IL-6. Strikingly, synergistic responses to costimulation with stem cell factor and IL-6 (but not G-CSF) are lost at higher concentrations in Socs3-deficient progenitor cells. Cytokine-induced expression of transcriptional regulators including cebpb, Ets2, Bcl3, c-Myc, Jun, and Fosl2 are differentially regulated in Socs3-deficient cells. The tight regulation by Socs3 of signal transducer and activator of transcription 3 phosphorylation and gene transcription after cytokine receptor ligation significantly influences the fate of myeloid progenitor cells.
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: Sam
authors.initials: S
authors.lastname: Wormald
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Hiu
authors.initials: H
authors.lastname: Kiu
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D015850:Interleukin-6; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor