Korean J Intern Med.  2010 Dec;25(4):429-435. 10.3904/kjim.2010.25.4.429.

Engagement of Toll-Like Receptor 3 Induces Vascular Endothelial Growth Factor and Interleukin-8 in Human Rheumatoid Synovial Fibroblasts

• Moon SJ
• Park MK
• Oh HJ
• Lee SY
• Kwok SK
• Cho ML
• Ju JH
• Park KS
• Kim HY
• Park SH

• KMID: 964725
• DOI: http://doi.org/10.3904/kjim.2010.25.4.429

Abstract

BACKGROUND/AIMS
Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS).
METHODS
FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry.
RESULTS
The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-kappaB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS.
CONCLUSIONS
Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-kappaB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.

Keyword

Toll-like receptor 3; Arthritis, rheumatoid; Vascular endothelial growth factor; Interleukin-8; Synovial fibroblast

MeSH Terms

Arthritis, Rheumatoid/drug therapy/*etiology/metabolism
Cells, Cultured
Fibroblasts/metabolism
Humans
Interleukin-8/analysis/*biosynthesis/genetics
NF-kappa B/physiology
Neovascularization, Pathologic/etiology
RNA, Messenger/analysis
Synovial Membrane/cytology/*metabolism
Toll-Like Receptor 3/analysis/*physiology
Vascular Endothelial Growth Factor A/analysis/*biosynthesis/genetics