Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways

• Published in: Immunology Letters 2006-03, Vol.103 (2), p.159-166
• Main Authors: Cho, Mi-La, Jung, Young Ok, Moon, Young-Mi, Min, So-Youn, Yoon, Chong-Hyeon, Lee, Sang-Heon, Park, Sung-Hwan, Cho, Chul-Soo, Jue, Dae-Myung, Kim, Ho-Youn
• Format: Article
• Language: English
• Subjects: Adult; Aged; AP-1; Arthritis, Rheumatoid - metabolism; Cells, Cultured; Curcumin - pharmacology; DNA - metabolism; Dose-Response Relationship, Drug; Female; Fibroblast-like synoviocytes; Fibroblasts - physiology; Humans; IL-18; Interleukin-18 - physiology; Male; Middle Aged; Protein Binding; Rheumatoid arthritis; RNA, Messenger - metabolism; Synovial Fluid - metabolism; Synovial Membrane - metabolism; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - physiology; Up-Regulation; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; VEGF
• ISSN: 0165-2478; 1879-0542; 1365-2567
• DOI: 10.1016/j.imlet.2005.10.020

Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In present study, we examined the effect of IL-18 on VEGF production in fibroblast-like synoviocytes (FLS) isolated from the patients with RA. FLS were prepared from the synovial tissues of patients with RA and osteoarthritis (OA) and cultured in the presence of IL-18. The production of VEGF from FLS was measured in culture supernatants by enzyme-linked immunosorbent assay (ELISA). The VEGF messenger RNA (mRNA) expression and AP-1 binding activity of VEGF transcript were determined by reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA). IL-18 and VEGF levels of sera and synovial fluids (SF) of RA patients ( n = 30) were significantly higher than those of OA patients ( n = 20). IL-18 dose-dependently increased the production of VEGF. The effect of IL-18 on VEGF production appeared to be as potent as IL-1β, whereas tumor necrosis factor (TNF)-α and interferon (IFN)-γ showed little effects on VEGF production. AP-1-specific inhibitor Curcumin dose-dependently abrogated the effect of IL-18 on VEGF production. The VEGF enhancement of IL-18 was associated with increased AP-1 binding activity to the VEGF promoter site. These findings suggest IL-18 as an angiogenic factor in RA and down-regulation of IL-18 activity or AP-1 signal pathway can be potential therapeutic targets for RA.