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

J Exp Med. 2003 Jun 2;197(11):1537-49. doi: 10.1084/jem.20021897.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Base Sequence
  • Cell Division
  • Cell Line
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC / metabolism
  • DNA / genetics
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Platelet Factor 4 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CXCR3
  • Receptors, Chemokine / genetics*
  • Receptors, Chemokine / metabolism*
  • Tissue Distribution
  • Transfection


  • CXCL11 protein, human
  • CXCL9 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Receptors, CXCR3
  • Receptors, Chemokine
  • Platelet Factor 4
  • DNA