Effect of interleukin‐4 on vascular endothelial growth factor production in rheumatoid synovial fibroblasts

Summary Interleukin (IL)‐4 has been demonstrated to have anti‐inflammatory and anti‐tumour activity. Because aberrant angiogenesis is a significant pathogenic component of tumour growth and chronic inflammation, we investigated the effect of IL‐4 on the production of vascular endothelial growth factor (VEGF) by synovial fibroblasts derived from patients with rheumatoid arthritis (RA). Fibroblast‐like synoviocytes (FLS) were prepared from synovial tissues of RA and incubated with different concentrations of IL‐4 in the presence or absence of transforming growth factor (TGF)‐β. VEGF level was measured by enzyme‐linked immunosorbent assay and semiquantitative reverse transcription–polymerase chain reaction. Treatment of FLS with IL‐4 alone caused a dose‐dependent increase in VEGF levels. In contrast, IL‐4 exhibited the inhibitory effect on VEGF production when FLS were stimulated with TGF‐β. Combined treatment of IL‐4 and IL‐10 inhibited TGF‐β‐induced VEGF production in an additive fashion. TGF‐β increased the induction of cyclooxygenase‐2 mRNA, which was inhibited significantly by the treatment of IL‐4. NS‐398, a COX‐2 inhibitor, inhibited TGF‐β‐induced VEGF production in a dose‐dependent manner. Furthermore, exogenous addition of prostaglandin E 2 (PGE 2 ) restored IL‐4 inhibition on TGF‐β induced VEGF production. Collectively, our results suggest that IL‐4 have an anti‐angiogenic effect, especially in the inflammatory milieu of RA by inhibiting the VEGF production in synovial fibroblasts.