Interleukin‐15 inhibits sodium nitroprusside–induced apoptosis of synovial fibroblasts and vascular endothelial cells

Abstract

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 upregulate 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.Conclusion. 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.

The anti-inflammatory potential of cefazolin as common gamma chain cytokine inhibitor

“…Recently, a key role for IL-2 acting in synergy with IL-1β in facilitating IL-17 production has been confirmed in pulmonary γδ T cells 27 . While these observations contrast from the data showing the limiting role of IL-2 in IL-17 production 28,29 , they also stress the necessity to define cefazolin action in more complex context of IL-17-producing helper T cell (Th17 cell) subset. Demonstration of anti-inflammatory effects of cefazolin may expedite possible future drug repositioning.…”

Il-15

“…For example, previous reports indicate that endothelial cells express IL-15 receptors and that IL-15 signaling is involved in the formation of new vasculature. 22, 23 IL-15 has also been shown to exhibit anabolic influences over skeletal muscle cells in vitro. 24 Moreover, IL-15 signaling has been shown to function as a protective agent against cell death in several immune and non-immune cell types.…”

Targeting Cytokines, Chemokines and Adhesion Molecules in Rheumatoid Arthritis

“…Moreover, compelling evidence from another study [30] demonstrated that IL-15 suppressed sodium nitroprussideinduced apoptosis in synovial fibroblast cultures and vascular endothelial cells grown on Matrigel whereas vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) production was unaffected. The results of this study [30] suggested that IL-15 could play a critical role in dampening the apoptotic cascade which could contribute to RA synovial apoptosis resistance [31] and stabilization of newly formed blood vessels [30] while also promoting RA synovial neoangiogenesis [32].…”

“…However, subsequent studies in RA showed that IL-15 synovial expression persisted even after TNFblockade [28] and although IL-15 employed at high doses was a pan-T cell growth factor [29] its inability to stimulate cytokine synthesis also indicated that IL-15 did not continuously drive antigen-specific T-cell proliferation [29]. Moreover, compelling evidence from another study [30] demonstrated that IL-15 suppressed sodium nitroprussideinduced apoptosis in synovial fibroblast cultures and vascular endothelial cells grown on Matrigel whereas vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) production was unaffected. The results of this study [30] suggested that IL-15 could play a critical role in dampening the apoptotic cascade which could contribute to RA synovial apoptosis resistance [31] and stabilization of newly formed blood vessels [30] while also promoting RA synovial neoangiogenesis [32].…”