The Journal of Experimental Medicine
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Published 2 June 2003. doi:10.1084/jem.20021897
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© Rockefeller University Press, 0022-1007/2003/6/1537 $5.00
The Journal of Experimental Medicine, Volume 197, Number 11, 1537-1549

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

Laura Lasagni1, Michela Francalanci1, Francesco Annunziato2, Elena Lazzeri2, Stefano Giannini1, Lorenzo Cosmi2, Costanza Sagrinati1, Benedetta Mazzinghi1, Claudio Orlando1, Enrico Maggi2, Fabio Marra2, Sergio Romagnani2, Mario Serio1 and Paola Romagnani1

1 Department of Clinical Pathophysiology, University of Florence, Florence 50139, Italy
2 Department of Internal Medicine, University of Florence, Florence 50139, Italy

Address correspondence to Paola Romagnani, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Phone: 390554271483; Fax: 390554271371; E-mail: p.romagnani{at}dfc.unifi.it

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.

Key Words: CXCR3-B • CXCR3-A • angiogenesis • chemokines • chemokines receptor


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