Nature Medicine
- 12, 1185 - 1190 (2006)
Published online: 17 September 2006; | doi:10.1038/nm1470
G-CSF induces E-selectin ligand expression on human myeloid cellsNilesh M Dagia1, 2, Samah Z Gadhoum1, 2, Christine A Knoblauch1, 2, Joel A Spencer3, Parisa Zamiri3, Charles P Lin3 & Robert Sackstein1, 2, 4, 51
Department of Dermatology, Brigham & Women's Hospital, 77 Avenue Louis Pasteur, Room 671, Harvard Medical School, Boston, Massachusetts 02115, USA
2
Harvard Skin Disease Research Center, 77 Avenue Louis Pasteur, Room 671, Harvard Medical School, Boston, Massachusetts 02115, USA. 3
Wellman Center for Photomedicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA. 4
Department of Medicine, Brigham & Women's Hospital, Dana-Farber Cancer Institute. 5
Department of Medical Oncology, Dana-Farber Cancer Institute.
Correspondence should be addressed to Robert Sackstein rsackstein@rics.bwh.harvard.edu Clinical use of G-CSF can result in vascular and inflammatory complications1,
2,
3,
4,
5,
6,
7. To investigate the molecular basis of these effects, we analyzed the adherence of G-CSF–mobilized human peripheral blood leukocytes (ML) to inflamed (TNF- –stimulated) vascular endothelium. Studies using parallel plate assays under physiologic flow conditions and intravital microscopy in a mouse inflammation model each showed that ML take part in heightened adhesive interactions with endothelium compared to unmobilized (native) blood leukocytes, mediated by markedly increased E-selectin receptor-ligand interactions. Biochemical studies showed that ML express the potent E-selectin ligand HCELL (ref. 8) and another, previously unrecognized  65-kDa E-selectin ligand, and possess enhanced levels of transcripts encoding glycosyltransferases (ST3GalIV, FucT-IV and FucT-VII) conferring glycan modifications associated with E-selectin ligand activity. Enzymatic treatments and physiologic binding assays showed that HCELL and the 65-kDa E-selectin ligand contribute prominently to the observed G-CSF–induced myeloid cell adhesion to inflamed endothelium. Treatment of normal human bone marrow cells with a pharmacokinetically relevant concentration of G-CSF in vitro
9,
10 resulted in increased expression of these two molecules, coincident with increased transcripts encoding pertinent glycosyltransferases and heightened E-selectin binding. These findings provide direct evidence for a role of G-CSF in the induction of E-selectin ligands on myeloid cells, thus providing mechanistic insight into the pathobiology of G-CSF complications.
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