Journal
JOURNAL OF IMMUNOLOGY
Volume 165, Issue 9, Pages 5269-5277Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.9.5269
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Funding
- NCI NIH HHS [CA87879, R01 CA034590-17, R01 CA034590-18] Funding Source: Medline
- NHLBI NIH HHS [HL66027] Funding Source: Medline
- NIDDK NIH HHS [DK38517] Funding Source: Medline
- BLRD VA [IK6 BX005225] Funding Source: Medline
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We have previously shown that members of the ELR+ CXC chemokine family, including IL-8; growth-related oncogenes alpha, beta, and gamma; 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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