Serpina1 Is a Potent Inhibitor of IL-8-Induced Hematopoietic Stem Cell Mobilization

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (5), p.1469-1474
• Main Authors: van Pel, Melissa, van Os, Ronald, Velders, Gerjo A., Hagoort, Henny, Heegaard, Peter M. H., Lindley, Ivan J. D., Willemze, Roel, Fibbe, Willem E.
• Format: Article
• Language: English
• Subjects: alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin - physiology; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - metabolism; Biological Sciences; Blood; Blotting, Western; Bone Marrow - pathology; Cell Adhesion; Cytokines; Cytokines - metabolism; Dose-Response Relationship, Radiation; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Interleukin-8 - antagonists & inhibitors; Interleukin-8 - metabolism; Irradiation; Male; Medical research; Messenger RNA; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Molecules; Neutrophils; Pancreatic Elastase - metabolism; Protease inhibitors; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Proteins; Quaternary ammonium compounds; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA, Messenger - metabolism; Serine proteinase inhibitors; Stem cells; Stem Cells - cytology; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510192103

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 cytokineinduced 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 Serpinal 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 Serpinal. To further study a possible in vivo role of Serpinal in HSC/HPC mobilization, we administered Serpinal before IL-8 injection. This administration resulted in an almost complete inhibition of HSC/HPC mobilization, whereas heat-inactivated Serpinal had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC/HPC mobilization and induces Serpinal in the BM. Because exogenous administration of Serpinal inhibits mobilization, we propose that radiation-induced Serpinal 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.