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

By L. Lasagni, M. Francalanci, F. Annunziato, E. Lazzeri, S. Giannini, L. Cosmi, C. Sagrinati, B. Mazzinghi, C. Orlando, E. Maggi and 4 more. Journal of Experimental Medicine, 2003

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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.

Subfields: Hematology, Immunology and Allergy, Oncology

View Paper: https://www.semanticscholar.org/paper/7f9ace8fd76c574d5ccb0f6092e0376562beca84

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In Oncology

1. A. Zlotnik
2. O. Yoshie
3. A. Rot
4. U. V. von Andrian
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6. Alexander Zarbock

Citations in the corpus

• International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors (2014, neutral): “The identification of an alternative splice variant of CXCR3, termed CXCR3-B, specifically in human endothelial cells, was suggested as a possible explanation for CXCL10’s angiostatic effects (Lasagni et al., 2003).”
• Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. (2004, background): “CXCL4, in addition to using CXCR3B (75), may also signal through chondroitin sulfate–decorated membrane molecules on neutrophils, monocytes, and lymphocytes (76).”
• Platelet-neutrophil-interactions: linking hemostasis and inflammation. (2007, background): “Endothelial CXCR3b, a splice variant of CXCR3, is a specific receptor for CXCL4 and may account for an angiostatic effect induced by activated platelets.(89) Chondroitin sulphate also binds CXCL4.”
• The chemokine and chemokine receptor superfamilies and their molecular evolution (2006, background): “The chemokines they encode function in T-cell recruitment through CXCR3 [28] and also in the negative control of angiogenesis through CXCR3B, an alternatively spliced variant of CXCR3 [29].”
• The Chemokine Superfamily Revisited (2012, neutral): “Although CXCR3-B (a CXCR3 slice variant) is believed to mediate the angiostatic activity of CXCL4 and other non-ELR CXC chemokines (CXCL9, CXCL10, CXCL11) (Lasagni et al., 2003), the mechanism remains unknown.”