title: G-CSF induces membrane expression of a myeloperoxidase glycovariant that operates as an E-selectin ligand on human myeloid cells.
abstract: The host defense response critically depends on the production of leukocytes by the marrow and the controlled delivery of these cells to relevant sites of inflammation/infection. The cytokine granulocyte-colony stimulating factor (G-CSF) is commonly used therapeutically to augment neutrophil recovery following chemo/radiation therapy for malignancy, thereby decreasing infection risk. Although best known as a potent inducer of myelopoiesis, we previously reported that G-CSF also promotes the delivery of leukocytes to sites of inflammation by stimulating expression of potent E-selectin ligands, including an uncharacterized ∼65-kDa glycoprotein. To identify this ligand, we performed integrated biochemical analysis and mass spectrometry studies of G-CSF-treated primary human myeloid cells. Our studies show that this novel E-selectin ligand is a glycoform of the heavy chain component of the enzyme myeloperoxidase (MPO), a well-known lysosomal peroxidase. This specialized MPO glycovariant, referred to as "MPO-E-selectin ligand" (MPO-EL), is expressed on circulating G-CSF-mobilized leukocytes and is naturally expressed on blood myeloid cells in patients with febrile leukocytosis. In vitro biochemical studies show that G-CSF programs MPO-EL expression on human blood leukocytes and marrow myeloid cells via induction of N-linked sialofucosylations on MPO, with concomitant cell surface display of the molecule. MPO-EL is catalytically active and mediates angiotoxicity on human endothelial cells that express E-selectin. These findings thus define a G-CSF effect on MPO chemical biology that endows unsuspected functional versatility upon this enzyme, unveiling new perspectives on the biology of G-CSF and MPO, and on the role of E-selectin receptor/ligand interactions in leukocyte migration and vascular pathology.
authors.affiliation: Departments of Dermatology andHarvard Skin Disease Research Center, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Silvescu
authors.affiliation: Departments of Dermatology andHarvard Skin Disease Research Center, Harvard Medical School, Boston, MA 02115; andMedicine, Brigham and Women's Hospital, Boston, MA 02115;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 rsackstein@partners.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Sackstein
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism*; D005643:Fucose / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D019040:E-Selectin; D008024:Ligands; D011134:Polysaccharides; D016179:Granulocyte Colony-Stimulating Factor; D005643:Fucose; D009195:Peroxidase; D019158:N-Acetylneuraminic Acid
keywords: glycosylation; hematopoietic stem cell transplantation; leukemia