Home LiteratureArticle Details
PMID: 12782716 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

The Journal of experimental medicine ·Vol. 197 ·No. 11 ·2003-06-02 ·Pages 1537-49

Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P

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.

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,metabolism Humans Intercellular Signaling Peptides and Proteins Molecular Sequence Data Neoplasms/genetics,immunology Platelet Factor 4/metabolism RNA, Messenger/genetics,metabolism Receptors, CXCR3 Receptors, Chemokine/genetics,metabolism Tissue Distribution Transfection
Chemicals
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
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Lasagni Laura
Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Francalanci Michela
Annunziato Francesco
Lazzeri Elena
Giannini Stefano
Cosmi Lorenzo
Sagrinati Costanza
Mazzinghi Benedetta
Orlando Claudio
Maggi Enrico
Marra Fabio
Romagnani Sergio
Serio Mario
Romagnani Paola
References (52)
52 references, click to expand
  1. Spatial and temporally restricted expression of chemokines and chemokine receptors in the developing human kidney.
    J Am Soc Nephrol. 2002 Apr;13(4):957-67 PMID: 11912255
  2. Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia.
    J Immunol. 2002 Apr 1;168(7):3221-6 PMID: 11907075
  3. Effects of interferon alpha on the expression of p21cip1/waf1 and cell cycle distribution in carcinoid tumors.
    Cancer Invest. 2002;20(3):348-56 PMID: 12025230
  4. Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' disease.
    Am J Pathol. 2002 Jul;161(1):195-206 PMID: 12107104
  5. Inhibition of endothelial cell survival and angiogenesis by protein kinase A.
    J Clin Invest. 2002 Oct;110(7):933-41 PMID: 12370271
  6. Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway.
    Blood. 2002 Nov 1;100(9):3087-94 PMID: 12384403
  7. CXC chemokines in angiogenesis related to pulmonary fibrosis.
    Chest. 2002 Dec;122(6 Suppl):298S-301S PMID: 12475804
  8. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves.
    Am J Physiol. 1978 Aug;235(2):E97-102 PMID: 686171
  9. Studies of human plate alpha-granule release in vivo.
    Blood. 1981 Sep;58(3):607-18 PMID: 6266431
  10. Potentiation of radiation cytotoxicity by recombinant interferons, a phenomenon associated with increased blockage at the G2-M phase of the cell cycle.
    Cancer Res. 1987 Aug 15;47(16):4338-41 PMID: 2440565
  11. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides.
    Science. 1990 Jan 5;247(4938):77-9 PMID: 1688470
  12. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity.
    Cancer Res. 1991 Apr 15;51(8):2077-83 PMID: 1706960
  13. HMEC-1: establishment of an immortalized human microvascular endothelial cell line.
    J Invest Dermatol. 1992 Dec;99(6):683-90 PMID: 1361507
  14. Characterization and species distribution of high affinity GTP-coupled receptors for human rantes and monocyte chemoattractant protein 1.
    J Exp Med. 1993 Mar 1;177(3):851-6 PMID: 7679712
  15. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation.
    J Exp Med. 1995 Jul 1;182(1):219-31 PMID: 7790818
  16. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms.
    J Biol Chem. 1995 Jun 23;270(25):15059-65 PMID: 7797488
  17. Interferon-inducible protein 10 and macrophage inflammatory protein-1 alpha inhibit growth factor stimulation of Raf-1 kinase activity and protein synthesis in a human growth factor-dependent hematopoietic cell line.
    J Biol Chem. 1995 Sep 15;270(37):21998-2007 PMID: 7545174
  18. Selective binding of platelet factor 4 to regions of active angiogenesis in vivo.
    Am J Physiol. 1995 Sep;269(3 Pt 2):H829-36 PMID: 7573524
  19. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis.
    J Biol Chem. 1995 Nov 10;270(45):27348-57 PMID: 7592998
  20. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes.
    J Exp Med. 1996 Sep 1;184(3):963-9 PMID: 9064356
  21. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases.
    J Exp Med. 1996 Sep 1;184(3):981-92 PMID: 9064358
  22. Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth.
    Nat Med. 1997 Apr;3(4):437-42 PMID: 9095178
  23. Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo.
    Blood. 1997 Apr 15;89(8):2635-43 PMID: 9108380
  24. Interferon-inducible protein-10 and lymphotactin induce the chemotaxis and mobilization of intracellular calcium in natural killer cells through pertussis toxin-sensitive and -insensitive heterotrimeric G-proteins.
    FASEB J. 1997 Aug;11(10):765-74 PMID: 9271361
  25. Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated mechanism.
    Diabetes. 1997 Nov;46(11):1881-7 PMID: 9356040
  26. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s.
    J Exp Med. 1998 Jan 5;187(1):129-34 PMID: 9419219
  27. New insights into the negative regulation of hematopoiesis by chemokine platelet factor 4 and related peptides.
    Blood. 1998 Apr 15;91(8):2772-80 PMID: 9531587
  28. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization.
    Blood. 1998 May 1;91(9):3289-99 PMID: 9558385
  29. High CD30 ligand expression by epithelial cells and Hassal's corpuscles in the medulla of human thymus.
    Blood. 1998 May 1;91(9):3323-32 PMID: 9558389
  30. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3.
    Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8205-10 PMID: 9653165
  31. Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(Cip1/WAF1).
    Blood. 1999 Jan 1;93(1):25-33 PMID: 9864142
  32. Angiotensin II stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells.
    J Am Soc Nephrol. 1999 Feb;10(2):245-55 PMID: 10215323
  33. Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors.
    J Immunol. 1999 Apr 1;162(7):3765-9 PMID: 10201891
  34. IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity.
    J Cell Biol. 1999 Jul 12;146(1):243-54 PMID: 10402474
  35. Inhibition of in vitro angiogenesis by platelet factor-4-derived peptides and mechanism of action.
    Blood. 1999 Aug 1;94(3):984-93 PMID: 10419890
  36. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes.
    J Exp Med. 1998 Mar 16;187(6):875-83 PMID: 9500790
  37. The N terminus of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity.
    J Biol Chem. 1999 Oct 29;274(44):31327-32 PMID: 10531332
  38. Role for interactions between IP-10/Mig and CXCR3 in proliferative glomerulonephritis.
    J Am Soc Nephrol. 1999 Dec;10(12):2518-26 PMID: 10589690
  39. Chemokines: a new classification system and their role in immunity.
    Immunity. 2000 Feb;12(2):121-7 PMID: 10714678
  40. The biology of chemokines and their receptors.
    Annu Rev Immunol. 2000;18:217-42 PMID: 10837058
  41. CXC chemokines in angiogenesis.
    J Leukoc Biol. 2000 Jul;68(1):1-8 PMID: 10914483
  42. Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells.
    Oncogene. 2000 Aug 3;19(33):3766-73 PMID: 10949931
  43. Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells.
    FASEB J. 2000 Oct;14(13):2055-64 PMID: 11023990
  44. Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity.
    J Clin Invest. 2001 Jan;107(1):53-63 PMID: 11134180
  45. The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model.
    Cancer Immunol Immunother. 2001 Jan;49(11):587-92 PMID: 11225989
  46. Signal transduction by the chemokine receptor CXCR3: activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes.
    J Biol Chem. 2001 Mar 30;276(13):9945-54 PMID: 11136732
  47. G-protein-coupled receptors and signaling networks: emerging paradigms.
    Trends Pharmacol Sci. 2001 Jul;22(7):368-76 PMID: 11431032
  48. Cutting edge: selective usage of chemokine receptors by plasmacytoid dendritic cells.
    J Immunol. 2001 Aug 15;167(4):1862-6 PMID: 11489962
  49. Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells.
    J Biol Chem. 2001 Sep 7;276(36):33805-11 PMID: 11448967
  50. Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment.
    J Exp Med. 2001 Nov 5;194(9):1375-84 PMID: 11696601
  51. IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide.
    J Am Soc Nephrol. 2002 Jan;13(1):53-64 PMID: 11752021
  52. Chemokines: agents for the immunotherapy of cancer?
    Nat Rev Immunol. 2002 Mar;2(3):175-84 PMID: 11913068
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20021897
Published
2003-06-02
Pages
1537-49
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193908
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20021897 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2