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

Mi La Cho, Young Ok Jung, Young Mi Moon, So Youn Min, Chong Hyeon Yoon, Sang Heon Lee, Sung Hwan Park, Chul Soo Cho, Dae Myung Jue, Ho Youn Kim

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)159-166
Number of pages8
JournalImmunology Letters
Volume103
Issue number2
DOIs
StatePublished - Mar 15 2006

Keywords

  • AP-1
  • Fibroblast-like synoviocytes
  • IL-18
  • Rheumatoid arthritis
  • VEGF

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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