The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published online 28 March 2005 doi:10.1084/jem.20042299
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 7, 1077-1088
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ARTICLE

 Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization

Ingrid G. Winkler1,2, Jean Hendy1, Paul Coughlin3, Anita Horvath3, and Jean-Pierre Lévesque1,2

1 Haematopoietic Stem Cell Laboratory, Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia
2 Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
3 Department of Medicine, Monash University, Box Hill Hospital, Box Hill, Victoria 3128, Australia

CORRESPONDENCE Jean-Pierre Lévesque: jplevesque{at}mmri.mater.org.au OR Ingrid G. Winkler: iwinkler{at}mmri.mater.org.au

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.

Abbreviations used: ß2m, ß2-microglobulin; CG, cathepsin G; CY, cyclophosphamide; HPC, hematopoietic progenitor cell; NE, neutrophil elastase.


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