title: Changes in Gene Expression during G-CSF-Induced Emergency Granulopoiesis in Humans.
abstract: Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for G-CSF as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been investigated in humans. In this work, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy individuals after 5 d of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNA was subjected to microarray analysis. mRNA levels were compared with previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. One thousand one hundred and ten mRNAs were differentially expressed >2-fold throughout terminal granulopoiesis. Major changes were seen in pathways involved in apoptosis, cytokine signaling, and TLR pathways. In addition, G-CSF treatment reduced the levels of four of five measured granule proteins in mature neutrophils, including the proantibacterial protein hCAP-18, which was completely deficient in neutrophils from G-CSF-treated donors. These results indicate that multiple biological processes are altered to satisfy the increased demand for neutrophils during G-CSF-induced emergency granulopoiesis in humans.
authors.affiliation: Granulocyte Research Laboratory, Department of Hematology, National University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark;
authors.forename: Corinna C
authors.identifier: 0000-0001-8838-6777
authors.initials: CC
authors.lastname: Pedersen
authors.affiliation: Center for Genomic Medicine, National University Hospital, DK-2100 Copenhagen, Denmark;
authors.forename: Rehannah
authors.initials: R
authors.lastname: Borup
authors.affiliation: Department of Clinical Immunology, Cell Therapy Facility, National University Hospital, DK-2100 Copenhagen, Denmark; and.
authors.forename: Anne
authors.initials: A
authors.lastname: Fischer-Nielsen
authors.affiliation: Granulocyte Research Laboratory, Department of Hematology, National University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark;
authors.forename: Helena
authors.identifier: 0000-0002-9050-0601
authors.initials: H
authors.lastname: Mora-Jensen
authors.affiliation: Biotech and Research Innovation Centre, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Fossum
authors.affiliation: Granulocyte Research Laboratory, Department of Hematology, National University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark; borregaard@rh.dk jack.cowland@regionh.dk.
authors.forename: Jack B
authors.identifier: 0000-0002-7429-5388
authors.initials: JB
authors.lastname: Cowland
authors.affiliation: Granulocyte Research Laboratory, Department of Hematology, National University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark; borregaard@rh.dk jack.cowland@regionh.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000276:immunology; D002465:Cell Movement; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D019891:Leukopoiesis / Q000235:genetics*; D046228:Microarray Analysis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D054804:Cathelicidins