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Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
Center for Vascular Biology and
Departments of Medicine and Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232;
§
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095;
¶
Theodor Kocher Institute, Universitat Bern, Bern, Switzerland; and
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Department of Veteran’s Affairs, Vanderbilt University Medical Center, Nashville, TN 37232
We have previously shown that members of the ELR+ CXC
chemokine family, including IL-8; growth-related oncogenes 
, ß,
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.
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A. L. Miller, R. M. Strieter, A. D. Gruber, S. B. Ho, and N. W. Lukacs CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction J. Immunol., March 15, 2003; 170(6): 3348 - 3356. [Abstract] [Full Text] [PDF]
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A. Li, S. Dubey, M. L. Varney, B. J. Dave, and R. K. Singh IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis J. Immunol., March 15, 2003; 170(6): 3369 - 3376. [Abstract] [Full Text] [PDF]
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J. Heidemann, H. Ogawa, M. B. Dwinell, P. Rafiee, C. Maaser, H. R. Gockel, M. F. Otterson, D. M. Ota, N. Lugering, W. Domschke, et al. Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2 J. Biol. Chem., February 28, 2003; 278(10): 8508 - 8515. [Abstract] [Full Text] [PDF]
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E. S. White, K. R. Flaherty, S. Carskadon, A. Brant, M. D. Iannettoni, J. Yee, M. B. Orringer, and D. A. Arenberg Macrophage Migration Inhibitory Factor and CXC Chemokine Expression in Non-Small Cell Lung Cancer: Role in Angiogenesis and Prognosis Clin. Cancer Res., February 1, 2003; 9(2): 853 - 860. [Abstract] [Full Text] [PDF]
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M. P. Keane, S. C. Donnelly, J. A. Belperio, R. B. Goodman, M. Dy, M. D. Burdick, M. C. Fishbein, and R. M. Strieter Imbalance in the Expression of CXC Chemokines Correlates with Bronchoalveolar Lavage Fluid Angiogenic Activity and Procollagen Levels in Acute Respiratory Distress Syndrome J. Immunol., December 1, 2002; 169(11): 6515 - 6521. [Abstract] [Full Text] [PDF]
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 R. M. Strieter, J. A. Belperio, and M. P. Keane CXC Chemokines in Angiogenesis Related to Pulmonary Fibrosis Chest, December 1, 2002; 122 (2009): 298S - 301S. [Abstract] [Full Text] [PDF]
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J. Middleton, A. M. Patterson, L. Gardner, C. Schmutz, and B. A. Ashton Leukocyte extravasation: chemokine transport and presentation by the endothelium Blood, December 1, 2002; 100(12): 3853 - 3860. [Abstract] [Full Text] [PDF]
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I. U. Schraufstatter, K. Trieu, L. Sikora, P. Sriramarao, and R. DiScipio Complement C3a and C5a Induce Different Signal Transduction Cascades in Endothelial Cells J. Immunol., August 15, 2002; 169(4): 2102 - 2110. [Abstract] [Full Text] [PDF]
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A. B. LENTSCH The Duffy antigen/receptor for chemokines (DARC) and prostate cancer. A role as clear as black and white? FASEB J, July 1, 2002; 16(9): 1093 - 1095. [Abstract] [Full Text] [PDF]
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 M. Gouwy, S. Struyf, F. Mahieu, W. Put, P. Proost, and J. Van Damme The Unique Property of the CC Chemokine Regakine-1 to Synergize with Other Plasma-Derived Inflammatory Mediators in Neutrophil Chemotaxis Does Not Reside in Its NH2-Terminal Structure Mol. Pharmacol., July 1, 2002; 62(1): 173 - 180. [Abstract] [Full Text] [PDF]
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K. Wakasugi, B. M. Slike, J. Hood, K. L. Ewalt, D. A. Cheresh, and P. Schimmel Induction of Angiogenesis by a Fragment of Human Tyrosyl-tRNA Synthetase J. Biol. Chem., May 31, 2002; 277(23): 20124 - 20126. [Abstract] [Full Text] [PDF]
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B. Endlich, D. Armstrong, J. Brodsky, M. Novotny, and T. A. Hamilton Distinct Temporal Patterns of Macrophage-Inflammatory Protein-2 and KC Chemokine Gene Expression in Surgical Injury J. Immunol., April 1, 2002; 168(7): 3586 - 3594. [Abstract] [Full Text] [PDF]
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S. S. Cheng, N. W. Lukacs, and S. L. Kunkel Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells J. Immunol., March 15, 2002; 168(6): 2887 - 2894. [Abstract] [Full Text] [PDF]
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C. Choi, O. Kutsch, J. Park, T. Zhou, D.-W. Seol, and E. N. Benveniste Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Caspase-Dependent Interleukin-8 Expression and Apoptosis in Human Astroglioma Cells Mol. Cell. Biol., February 1, 2002; 22(3): 724 - 736. [Abstract] [Full Text] [PDF]
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 C. Sachidanandan, R. Sambasivan, and J. Dhawan Tristetraprolin and LPS-inducible CXC chemokine are rapidly induced in presumptive satellite cells in response to skeletal muscle injury J. Cell Sci., January 7, 2002; 115(13): 2701 - 2712. [Abstract] [Full Text] [PDF]
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P. Proost, E. Schutyser, P. Menten, S. Struyf, A. Wuyts, G. Opdenakker, M. Detheux, M. Parmentier, C. Durinx, A.-M. Lambeir, et al. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties Blood, December 15, 2001; 98(13): 3554 - 3561. [Abstract] [Full Text] [PDF]
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L. W. Shepard, M. Yang, P. Xie, D. D. Browning, T. Voyno-Yasenetskaya, T. Kozasa, and R. D. Ye Constitutive Activation of NF-kappa B and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Galpha 13 and RhoA J. Biol. Chem., November 30, 2001; 276(49): 45979 - 45987. [Abstract] [Full Text] [PDF]
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