Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor.
Mobilized progenitor cells currently represent the most commonly used source of hematopoietic progenitor cells (HPCs) to effect hematopoietic reconstitution following myeloablative chemotherapies. Despite their widespread use, the molecular mechanisms responsible for the enforced egress of HPCs from the bone marrow (BM) into the circulation in response to mobilizing agents such as cytokines remain to be determined. Results of this study indicate that expression of vascular cell adhesion molecule-1 (VCAM-1) is strongly reduced in vivo in the BM during HPC mobilization by granulocyte colony-stimulating factor (G-CSF) and stem cell factor. Two serine proteases, namely, neutrophil elastase and cathepsin G, were identified, which cleave VCAM-1 and are released by neutrophils accumulating in the BM during the course of immobilization induced by G-CSF. The proposal is made that an essential step contributing to the mobilization of HPCs is the proteolytic cleavage of VCAM-1 expressed by BM stromal cells, an event triggered by the degranulation of neutrophils accumulating in the BM in response to the administration of G-CSF.
Lévesque
J P
JP
Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia. jp.levesque@pmci.unimelb.edu.au
Takamatsu
Y
Y
Nilsson
S K
SK
Haylock
D N
DN
Simmons
P J
PJ
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D012995:Solubility; D019089:Stem Cell Factor / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D017077:Culture Media, Conditioned; D019012:Integrin beta1; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; D019272:Leukocyte Elastase