title: G-CSF-activated STAT3 enhances production of the chemokine MIP-2 in bone marrow neutrophils.
abstract: Neutrophil mobilization from the bone marrow is a critical aspect of the innate immune response, enabling a rapid deployment of phagocytes to infected or inflamed tissue. The cytokine G-CSF, which is induced rapidly during infection, elicits a swift and potent mobilizing response, yet its mechanisms of action remain poorly understood. Here, we studied the role of G-CSF and its principal signal transducer STAT3 in regulating expression of the neutrophil chemoattractant MIP-2. Our studies revealed Gr-1(hi) mature neutrophils as major sources of Cxcl2 (MIP-2) mRNA in bone marrow and G-CSF-responsive MIP-2 protein production. Induction of Cxcl2 was regulated directly by G-CSF-activated STAT3 via interaction at a STAT consensus element in the Cxcl2 promoter. G-CSF coordinately stimulated the association of STAT3, induction of the transcriptionally active H3K4me3 modification, and recruitment of RNA Pol II at the Cxcl2 proximal promoter, as well as the promoter region of Il8rb, encoding the MIP-2 receptor. These results suggest that the G-CSF-STAT3 pathway directly regulates transcriptional events that induce neutrophil mobilization.
authors.affiliation: Department of Immunology and Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hoainam T
authors.initials: HT
authors.lastname: Nguyen-Jackson
authors.forename: Haiyan S
authors.initials: HS
authors.lastname: Li
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Erika
authors.initials: E
authors.lastname: Ohashi
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D054426:Chemokine CXCL2; D006657:Histones; D011956:Receptors, Cell Surface; D023063:Receptors, Interleukin-8B; D050796:STAT3 Transcription Factor; C551746:granulocyte receptor 1, mouse; D016179:Granulocyte Colony-Stimulating Factor; D012319:RNA Polymerase II