An Alternatively Spliced Variant of CXCR3 Mediates the Inhibition of Endothelial Cell Growth Induced by IP10, Mig, and I-TAC, and Acts as Functional Receptor for Platelet Factor 4 (original) (raw)
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F1000 - Post-publication peer review of the biomedical literature, 2003
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.
An alternatively spliced variant of CXCR3 mediates the inhibition of …
Journal of …, 2003
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– ...
2000
We have previously shown that members of the ELR ؉ CXC chemokine family, including IL-8; growth-related oncogenes ␣, , and ␥; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR ؉ CXC chemokines has not been determined. Because all ELR ؉ CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR ؉ CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR ؉ CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR ؉ CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2 ؊/؊ mice. We thus conclude that CXCR2 is the receptor responsible for ELR ؉ CXC chemokine-mediated angiogenesis.
Blood, 2010
We investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells. Labeled CXCL4L1 also bound to CXCR3A- and CXCR3B-transfectants and was displaced by CXCL4L1, CXCL4, and CXCL10. The CXCL4L1 anti-angiogenic activity was blocked by anti-CXCR3 antibodies (Abs) in the Matrigel and cornea micropocket assays. CXCL4L1 application in CXCR3−/− or in wild-type mice treated with neutralizing anti-CXCR3 Abs, resulted in reduced inhibitory activity of CXCL4L1 on tumor growth and vascularization of Lewis lung carcinoma. Furthermore, CXCL4L1 and CXCL4 chemoattracted activated T cells, human natural killer cells, and human immature dendritic cells (DCs). Migration of DCs toward CXCL4 and CXCL4L1 was desensitized by prei...
The Journal of Immunology, 2000
We have previously shown that members of the ELR ؉ CXC chemokine family, including IL-8; growth-related oncogenes ␣, , and ␥; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR ؉ CXC chemokines has not been determined. Because all ELR ؉ CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR ؉ CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR ؉ CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR ؉ CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR ؉ CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2 ؊/؊ mice. We thus conclude that CXCR2 is the receptor responsible for ELR ؉ CXC chemokine-mediated angiogenesis.
CXCR4-CXCL12-Dependent Inflammatory Network and Endothelial Progenitors
Current Medicinal Chemistry, 2010
The endothelial progenitor cells (EPCs) are angiogenic cells having properties similar to those of embryonal angioblasts. The number and function of EPCs are affected by a variety of conditions, including cytokines and chemokines, which are pivotal inflammatory signaling molecules. The purpose of this paper is to review current knowledge about the role of these progenitor in different vascular diseases, emphasizing the important biological role played from the CXCR4-CXCL12 axis in the cellular trafficking. Indeed, as described in detail in this review, the CXCR4/CXCL12 interaction produces pleiotropic effects in stem cells and plays a pivotal role in several processes related to development, tissue regeneration and development/progression of malignancies.
CXCR4 and cancer: CXCR4 and cancer
Pathology International, 2010
The chemokine receptor CXCR4 belongs to the large superfamily of G-protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoiesis, and immunity. Recent evidence has highlighted the role of CXCR4 in a variety of diseases including cancer and WHIM syndrome. Expression of CXCR4 in cancer metastasis appears to be due to dysregulation of the receptor leading to enhanced signaling. CXCR4 was also found to be a prognostic marker in various types of cancer including leukemia and breast cancer. These observations reveal that CXCR4 is an important molecule involved in several aspects of cancer progression. The SDF-1-CXCR4 axis is also involved in normal stem cell homing. Interestingly, cancer stem cells also express CXCR4 suggesting that the SDF-1-CXCR4 axis directs their trafficking/metastasis to organs that highly express SDF-1 such as the lymph nodes, lungs, liver, and bones. Here, we review what is currently known regarding the regulation of CXCR4 and how dysregulation contributes to disease progression. The Chemokine Receptor CXCR4 and Cancer The human chemokine system currently includes more than 40 chemokines and 18 chemokine receptors (Table 1). Chemokine receptors are defined by their ability to induce directional migration of cells toward a gradient of a chemotactic cytokine (chemotaxis). Chemokine receptors belong to a family of 7 transmembrane domain, G-protein-coupled cell surface receptors (GPCR) and the ligands are classified into four groups (CXC, CC, C, and CX 3 C) based on the position of the first two cysteines [1, 2]. Chemokine receptors are present on many different cell types. Initially, these receptors were identified on