Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint

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Abstract
Objective Angiogenesis, the growth of new blood vessels, is vital to the ingress of inflammatory leukocytes in rheumatoid arthritis (RA) synovial tissue and to the growth and proliferation of RA pannus. The factors that mediate the growth of new blood vessels have not been completely defined. This study examined the ability of Glu‐Leu‐Arg (ELR)–containing chemokines to induce angiogenesis in the RA joint. Methods To reflect angiogenic activity in vivo, we selected a model using whole human synovial tissue rather than isolated cells. Tissues were examined by immunohistochemistry and enzyme‐linked immunosorbent assay, and tissue homogenates were immunoneutralized and assayed for their ability to induce endothelial cell chemotaxis and rat corneal neovascularization. Results Cells expressing interleukin‐8 (IL‐8) and epithelial neutrophil activating peptide 78 (ENA‐78) were located in proximity to factor VIII–related antigen–immunopositive endothelial cells. RA homogenates produced more IL‐8 and ENA‐78 compared with normal synovial tissue homogenates. Moreover, homogenates from RA synovial tissue produced significantly more chemotactic activity for endothelial cells in vitro and angiogenic activity in the rat cornea in vivo than did normal synovial tissue homogenates. The effects of IL‐8 and ENA‐78 accounted for a significant proportion of the chemotactic activity of endothelial cells and angiogenic activity found in RA synovial tissue homogenates. Conclusion These results indicate that the ELR‐containing chemokines IL‐8 and ENA‐78 are important contributors to the angiogenic activity found in the inflamed RA joint. It is possible that efforts aimed at down‐regulating these chemokines offer a novel targeted therapy for the treatment of RA.