Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization.
Mobilization of hematopoietic progenitor cells into the blood involves a massive release of neutrophil serine proteases in the bone marrow. We hypothesize that the activity of these neutrophil serine proteases is regulated by the expression of naturally occurring inhibitors (serpina1 and serpina3) produced locally within the bone marrow. We found that serpina1 and serpina3 were transcribed in the bone marrow by many different hematopoietic cell populations and that a strong reduction in expression occurred both at the protein and mRNA levels during mobilization induced by granulocyte colony-stimulating factor or chemotherapy. This decreased expression was restricted to the bone marrow as serpina1 expression was maintained in the liver, leading to no change in plasma concentrations during mobilization. The down-regulation of serpina1 and serpina3 during mobilization may contribute to a shift in the balance between serine proteases and their inhibitors, and an accumulation of active neutrophil serine proteases in bone marrow extravascular fluids that cleave and inactivate molecules essential to the retention of hematopoietic progenitor cells within the bone marrow. These data suggest an unexpected role for serpina1 and serpina3 in regulating the bone marrow hematopoietic microenvironment as well as influencing the migratory behavior of hematopoietic precursors.
Winkler
Ingrid G
IG
Haematopoietic Stem Cell Laboratory, Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia. iwinkler@mmri.mater.org.au
Hendy
Jean
J
Coughlin
Paul
P
Horvath
Anita
A
Lévesque
Jean-Pierre
JP
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D045604:Extracellular Fluid / Q000378:metabolism; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism* / Q000502:physiology
D009841:Oligonucleotides; D012333:RNA, Messenger; C043392:SERPINA1 protein, human; D015843:Serpins; D019010:Vascular Cell Adhesion Molecule-1; D000515:alpha 1-Antitrypsin; D016179:Granulocyte Colony-Stimulating Factor