Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis

Abstract

Objective To characterize the expression of interleukin‐7 (IL‐7) and IL‐7 receptor (IL‐7R) in rheumatoid arthritis (RA) synovial tissue and to examine their regulation and pathogenic role in macrophages, endothelial cells, and synovial tissue fibroblasts in RA. Methods Expression of IL‐7 and IL‐7R in RA and normal synovial tissue was demonstrated by immunohistochemistry. Expression and regulation of IL‐7 and IL‐7R in RA peripheral blood in vitro–differentiated macrophages, RA synovial tissue fibroblasts, and human microvascular endothelial cells (HMVECs) were determined by real‐time reverse transcription–polymerase chain reaction and/or flow cytometry. Enzyme‐linked immunosorbent assay was used to examine production of proangiogenic factors by IL‐7–activated macrophages, RA fibroblasts, and endothelial cells. Results IL‐7 and IL‐7R were coexpressed on RA synovial tissue lining and sublining macrophages and endothelial cells. Expression of IL‐7 and its receptor was significantly elevated in RA synovial fluid and peripheral blood macrophages as well as RA fibroblasts, compared to normal cells. Toll‐like receptor 4 ligation (with lipopolysaccharide) and tumor necrosis factor α (TNFα) stimulation modulated expression of IL‐7 and IL‐7R on RA macrophages and HMVECs. However, in RA fibroblasts, lipopolysaccharide and TNFα activation increased expression of IL‐7R only. IL‐7 also mediated RA pathogenesis by inducing production of potent proangiogenic factors from macrophages and endothelial cells. Conclusion We have identified, for the first time, regulators of IL‐7 and IL‐7R expression in RA fibroblasts, RA peripheral blood in vitro–differentiated macrophages, and endothelial cells. Our results document a novel role of IL‐7 in RA angiogenesis.