Interleukin-15 inhibits sodium nitroprusside-induced apoptosis of synovial fibroblasts and vascular endothelial cells.
OBJECTIVE
One of the pathologic hallmarks of juvenile rheumatoid arthritis (JRA) is a tumor-like expansion of inflamed synovial tissue, or pannus, which causes much of the joint damage in this disease. The expansion of pannus is supported by extensive formation of new blood vessels. We have previously shown that revascularization of minced JRA synovial tissues engrafted into SCID mice correlated with the intensity of inflammatory activity in the tissues and with interleukin-15 (IL-15) expression. Since synovial vascular endothelial cells (VECs) expressed IL-15 receptors, the present study was undertaken to investigate the hypothesis that IL-15 might play a role in neovascularization of the pannus.


METHODS
To evaluate IL-15 for possible angiogenic activity, we assessed the ability of recombinant human IL-15 (rHuIL-15) to induce VEC growth directly and to stimulate synovial cells to produce endothelial growth factors. Since IL-15 had been shown to inhibit apoptosis of certain immune cells, we were also interested in whether it might have similar effects on VECs. Apoptosis was induced by addition of sodium nitroprusside (SNP) at 1-2 mM to >80% confluent primary VECs, and numbers of apoptotic cells were determined by annexin V assay.


RESULTS
Addition of rHuIL-15 at 10-100 ng/ml to primary synovial fibroblast cultures failed to up-regulate expression of vascular endothelial growth factor and angiopoietin 1 by these cells. Although rHuIL-15 failed to induce a mitogenic response of VECs, it promoted survival of these cells on Matrigel. Preincubation of VECs with rHuIL-15 at 50 ng/ml significantly reduced the proportion of VECs undergoing apoptosis.


CONCLUSIONS
IL-15 promotes survival of VECs on Matrigel and inhibits SNP-induced apoptosis of endothelial cells. We hypothesize that this mechanism may be relevant to the stabilization of newly formed vascular structures in JRA synovium.
Yang
Lin
L
Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Thornton
Sherry
S
Grom
Alexei A
AA
D017209:Apoptosis / Q000502:physiology*; D001171:Arthritis, Juvenile / Q000503:physiopathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019409:Interleukin-15 / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology*
D019409:Interleukin-15; D009599:Nitroprusside