title: An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.
abstract: The chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC regulate lymphocyte chemotaxis, mediate vascular pericyte proliferation, and act as angiostatic agents, thus inhibiting tumor growth. These multiple activities are apparently mediated by a unique G protein-coupled receptor, termed CXCR3. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including a powerful angiostatic effect, but its specific receptor is still unknown. Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4. Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. Overexpression of CXCR3-A induced an increase of survival, whereas overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways. Remarkably, primary cultures of human microvascular endothelial cells, whose growth is inhibited by CXCL9, CXCL10, CXCL11, and CXCL4, expressed CXCR3-B, but not CXCR3-A. Finally, monoclonal antibodies raised to selectively recognize CXCR3-B reacted with endothelial cells from neoplastic tissues, providing evidence that CXCR3-B is also expressed in vivo and may account for the angiostatic effects of CXC chemokines.
authors.affiliation: Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lasagni
authors.forename: Michela
authors.initials: M
authors.lastname: Francalanci
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.forename: Elena
authors.initials: E
authors.lastname: Lazzeri
authors.forename: Stefano
authors.initials: S
authors.lastname: Giannini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Costanza
authors.initials: C
authors.lastname: Sagrinati
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.forename: Claudio
authors.initials: C
authors.lastname: Orlando
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D010978:Platelet Factor 4 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D010978:Platelet Factor 4; D004247:DNA