title: Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization.
abstract: Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokine-induced HSC/HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC/HPC mobilization. Bone marrow (BM) extracellular extracts that were obtained from murine femurs after 0.5 Gy of TBI contained an inhibitor of elastase. Also, after low-dose TBI, both Serpina1 mRNA and protein concentrations were increased in BM extracts, compared with extracts that were obtained from controls. The inhibitory activity in BM extracts of irradiated mice was reversed by addition of an Ab directed against Serpina1. To further study a possible in vivo role of Serpina1 in HSC/HPC mobilization, we administered Serpina1 before IL-8 injection. This administration resulted in an almost complete inhibition of HSC/HPC mobilization, whereas heat-inactivated Serpina1 had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC/HPC mobilization and induces Serpina1 in the BM. Because exogenous administration of Serpina1 inhibits mobilization, we propose that radiation-induced Serpina1 is responsible for the inhibition of HSC/HPC mobilization. Also, we hypothesize that cytokine-induced HSC/HPC mobilization is determined by a critical balance between serine proteases and serine protease inhibitors.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: van Pel
authors.forename: Ronald
authors.initials: R
authors.lastname: van Os
authors.forename: Gerjo A
authors.initials: GA
authors.lastname: Velders
authors.forename: Henny
authors.initials: H
authors.lastname: Hagoort
authors.forename: Peter M H
authors.initials: PM
authors.lastname: Heegaard
authors.forename: Ivan J D
authors.initials: IJ
authors.lastname: Lindley
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: Willem E
authors.initials: WE
authors.lastname: Fibbe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010196:Pancreatic Elastase / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D016209:Interleukin-8; D011480:Protease Inhibitors; D012333:RNA, Messenger; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase