Yang Lin, Thornton Sherry, Grom Alexei A
Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Arthritis Rheum. 2002 Nov;46(11):3010-4. doi: 10.1002/art.10610.
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.
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.
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.
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.
幼年类风湿性关节炎（JRA）的病理特征之一是炎症滑膜组织（即血管翳）呈肿瘤样增生，这是该疾病中大部分关节损伤的原因。血管翳的增生由广泛的新血管形成所支持。我们之前已表明，移植到SCID小鼠体内的切碎的JRA滑膜组织的血管再生与组织中的炎症活动强度以及白细胞介素-15（IL-15）表达相关。由于滑膜血管内皮细胞（VECs）表达IL-15受体，因此开展本研究以探讨IL-15可能在血管翳新生血管形成中发挥作用这一假说。
为评估IL-15是否具有潜在的血管生成活性，我们评估了重组人IL-15（rHuIL-15）直接诱导VEC生长以及刺激滑膜细胞产生内皮生长因子的能力。由于已表明IL-15可抑制某些免疫细胞的凋亡，我们还想了解它对VECs是否可能有类似作用。通过向汇合度>80%的原代VECs中添加1-2 mM硝普钠（SNP）来诱导凋亡，并通过膜联蛋白V检测法确定凋亡细胞数量。
向原代滑膜成纤维细胞培养物中添加10-100 ng/ml的rHuIL-15未能上调这些细胞中血管内皮生长因子和血管生成素1的表达。尽管rHuIL-15未能诱导VECs产生促有丝分裂反应，但它促进了这些细胞在基质胶上的存活。用50 ng/ml的rHuIL-15对VECs进行预孵育可显著降低发生凋亡的VECs比例。
IL-15促进VECs在基质胶上的存活并抑制SNP诱导的内皮细胞凋亡。我们推测该机制可能与JRA滑膜中新形成的血管结构的稳定有关。
