title: Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation.
abstract: The Epstein-Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK682753A, which blocks oxysterol-induced G-protein activation, β-arrestin recruitment and B-cell chemotaxis. We furthermore demonstrate that activation triggers pertussis toxin-sensitive MAP kinase phosphorylation, which is also inhibited by GSK682753A. Thus, EBI2 signalling in B cells mediates key phenotypic functions via signalling pathways amenable to manipulation providing additional therapeutic options for inhibiting EBI2 activity.
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Tau
authors.initials: T
authors.lastname: Benned-Jensen
authors.forename: Christian M
authors.initials: CM
authors.lastname: Madsen
authors.forename: Kristine N
authors.initials: KN
authors.lastname: Arfelt
authors.forename: Christian
authors.initials: C
authors.lastname: Smethurts
authors.forename: Andy
authors.initials: A
authors.lastname: Blanchard
authors.forename: Robert
authors.initials: R
authors.lastname: Jepras
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
keywords: 7TM receptors; 7TM, seven-transmembrane; 7α,25-OHC, 7α,25-dihydroxycholesterol; Antagonism; EBI2; EBI2, Epstein–Barr virus induced gene 2; Epstein–Barr virus; MAP kinase activation; OE, over-expression; Oxysterols; PTLD, post transplantation lymphoproliferative disorder; ptx, pertussis toxin.