title: Base-modified UDP-sugars reduce cell surface levels of P-selectin glycoprotein 1 (PSGL-1) on IL-1β-stimulated human monocytes.
abstract: P-selectin glycoprotein ligand-1 (PSGL-1, CD162) is a cell-surface glycoprotein that is expressed, either constitutively or inducibly, on all myeloid and lymphoid cell lineages. PSGL-1 is implicated in cell-cell interactions between platelets, leukocytes and endothelial cells, and a key mediator of inflammatory cell recruitment and transmigration into tissues. Here, we have investigated the effects of the β-1,4-galactosyltransferase inhibitor 5-(5-formylthien-2-yl) UDP-Gal (5-FT UDP-Gal, compound 1: ) and two close derivatives on the cell surface levels of PSGL-1 on human peripheral blood mononuclear cells (hPBMCs). PSGL-1 levels were studied both under basal conditions, and upon stimulation of hPBMCs with interleukin-1β (IL-1β). Between 1 and 24 hours after IL-1β stimulation, we observed initial PSGL-1 shedding, followed by an increase in PSGL-1 levels on the cell surface, with a maximal window between IL-1β-induced and basal levels after 72 h. All three inhibitors reduce PSGL-1 levels on IL-1β-stimulated cells in a concentration-dependent manner, but show no such effect in resting cells. Compound 1: also affects the cell surface levels of adhesion molecule CD11b in IL-1β-stimulated hPBMCs, but not of glycoproteins CD14 and CCR2. This activity profile may be linked to the inhibition of global Sialyl Lewis presentation on hPBMCs by compound 1: , which we have also observed. Although this mechanistic explanation remains hypothetical at present, our results show, for the first time, that small molecules can discriminate between IL-1β-induced and basal levels of cell surface PSGL-1. These findings open new avenues for intervention with PSGL-1 presentation on the cell surface of primed hPBMCs and may have implications for anti-inflammatory drug development.
authors.affiliation: Sackler Institute of Pulmonary Pharmacology.|Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Varsha
authors.initials: V
authors.lastname: Kanabar
authors.affiliation: Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.|Department of Chemistry, Faculty of Natural & Mathematical Sciences, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Tedaldi
authors.affiliation: Department of Chemistry, Faculty of Natural & Mathematical Sciences, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
authors.forename: Jingqian
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Sackler Institute of Pulmonary Pharmacology.|Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Nie
authors.affiliation: Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Irina
authors.initials: I
authors.lastname: Panina
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Descroix
authors.affiliation: Sackler Institute of Pulmonary Pharmacology.|Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Francis
authors.initials: F
authors.lastname: Man
authors.affiliation: Sackler Institute of Pulmonary Pharmacology.|Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Pitchford
authors.affiliation: Sackler Institute of Pulmonary Pharmacology.|Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.affiliation: Department of Chemistry, Faculty of Natural & Mathematical Sciences, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK gerd.wagner@kcl.ac.uk.
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
mesh_terms: D002236:Carbohydrate Conformation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014539:Uridine Diphosphate Sugars / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D014539:Uridine Diphosphate Sugars
keywords: P-selectin glycoprotein-1; glycosyltransferase; inhibitor; interleukin-1β; monocytes