title: SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colony-stimulating factor receptor signaling.
abstract: The suppressor of cytokine signaling-3 (SOCS3/CIS3) has been shown to be an important negative regulator of cytokines, especially cytokines that activate STAT3. To examine the role of SOCS3 in neutrophils and the granulocyte colony-stimulating factor (G-CSF) signaling in vivo, we compared neutrophils from two types of conditional knockout mice, LysM-Cre:SOCS3(fl/fl) mice and Tie2-Cre:SOCS3(fl/fl) mice, in which the Socs3 gene had been deleted in mature neutrophils and hematopoietic stem cells, respectively. The size of the G-CSF-dependent colonies from Tie2-Cre:SOCS3(fl/fl) mouse bone marrow was much larger than that of colonies from control wild-type mice, while the size of interleukin-3-dependent colonies was similar. Moreover, LysM-Cre:SOCS3(fl/fl) mice had more neutrophils than SOCS3(fl/fl) mice, suggesting that SOCS3 is a negative regulator of G-CSF signaling in neutrophils. Consistent with this notion, G-CSF-induced STAT3 as well as mitogen-activated protein kinase activation was much stronger and prolonged in SOCS3-deficient mature neutrophils than in wild-type neutrophils. The preventive effect of G-CSF on apoptosis was more prominent in SOCS3-deficient mature neutrophils than in control neutrophils. These data indicate that SOCS3 negatively regulates granulopoiesis and G-CSF signaling in neutrophils and may contribute to neutrophilia or neutropenia.
authors.affiliation: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Ichiko
authors.initials: I
authors.lastname: Kinjyo
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mashima
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002633:Chemotaxis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005091:Exons; D005434:Flow Cytometry; D017353:Gene Deletion; D006098:Granulocytes / Q000502:physiology*; D007377:Interleukin-3 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008957:Models, Genetic; D009504:Neutrophils / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases