title: CCR3 expression induced by IL-2 and IL-4 functioning as a death receptor for B cells.
abstract: We report that CCR3 is not expressed on freshly isolated peripheral and germinal B cells, but is up-regulated after stimulation with IL-2 and IL-4 (approximately 98% CCR3(+)). Ligation of CCR3 by eotaxin/chemokine ligand (CCL) 11 induces apoptosis in IL-2- and IL-4-stimulated primary CD19(+) (approximately 40% apoptotic cells) B cell cultures as well as B cell lines, but has no effect on chemotaxis or cell adhesion. Freshly isolated B cells express low levels of CD95 and CD95 ligand (CD95L) (19 and 21%, respectively). Expression is up-regulated on culture in the presence of a combination of IL-2, IL-4, and eotaxin/CCL11 (88% CD95 and 84% CD95L). We therefore propose that ligation of such newly induced CCR3 on peripheral and germinal B cells by eotaxin/CCL11 leads to the enhanced levels of CD95 and CD95L expression. Ligation of CD95 by its CD95L expressed on neigboring B cells triggers relevant death signaling pathways, which include an increase in levels of Bcl-2 expression, its functional activity, and the release of cytochrome c from the mitochondria into the cytosol. These events initiate a cascade of enzymatic processes of the caspase family, culminating in programmed cell death. Interaction between CCR3 and eotaxin/CCL11 may, besides promoting allergic reactions, drive activated B cells to apoptosis, thereby reducing levels of Ig production, including IgE, and consequently limit the development of the humoral immune response. The apoptotic action of eotaxin/CCL11 suggests a therapeutic modality in the treatment of B cell lymphoma.
authors.affiliation: Biological Allergy Research, Hørsholm, Denmark. Tji@dk.alk.abello.com
authors.forename: Tan
authors.initials: T
authors.lastname: Jinquan
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Jacobi
authors.forename: Chen
authors.initials: C
authors.lastname: Jing
authors.forename: Anders
authors.initials: A
authors.lastname: Millner
authors.forename: Eva
authors.initials: E
authors.lastname: Sten
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Liu
authors.initials: L
authors.lastname: Anting
authors.forename: Lars P
authors.initials: LP
authors.lastname: Ryder
authors.forename: Christian
authors.initials: C
authors.lastname: Glue
authors.forename: Per S
authors.initials: PS
authors.lastname: Skov
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jarman
authors.forename: Kasper
authors.initials: K
authors.lastname: Lamberth
authors.forename: Hans-Jørgen
authors.initials: HJ
authors.lastname: Malling
authors.forename: Lars K
authors.initials: LK
authors.lastname: Poulsen
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002648:Child; D053222:Fas Ligand Protein; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014066:Palatine Tonsil; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D015847:Interleukin-4