Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta.
OBJECTIVE
To study the mechanism by which hypoxia and inflammatory cytokines mediate angiogenesis in the rheumatoid pannus through their effects on the fibroblast-like type B synoviocyte, the major cell type of normal synovia.


METHODS
Fibroblasts were prepared from synovial tissue of healthy and diseased individuals, and cultured in the presence of various stimuli. The expression of vascular endothelial growth factor (VEGF) was assessed by ELISA and reverse transcription polymerase chain reaction.


RESULTS
Unlike normal fibroblasts, synovial fibroblasts from rheumatoid arthritis (RA) and osteoarthritis constitutively secreted significant levels of VEGF, which is known to act directly on endothelial cells. VEGF secretion was further inducible by both hypoxia and interleukin 1beta (IL-1beta) and these increases were additive. In contrast, tumor necrosis factor alpha was unable to induce VEGF expression.


CONCLUSIONS
Under hypoxia or IL-1 stimulation, conditions common to the inflamed synovium, type B synoviocytes secrete increased levels of VEGF, which is likely to act on nearby endothelia, promoting angiogenesis. The constitutive expression of VEGF in rheumatoid synovial fibroblasts may reflect an altered phenotype involved in the pathology of RA.
Jackson
J R
JR
Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Minton
J A
JA
Ho
M L
ML
Wei
N
N
Winkler
J D
JD
D017398:Alternative Splicing / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010003:Osteoarthritis / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007375:Interleukin-1; D016209:Interleukin-8; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors