Department of Internal Medicine and Rheumatology, Justus-Liebig University Giessen, and the Kerckhoff Klinik, D-61231 Bad Nauheim, Germany.
J Biol Chem. 2012 Aug 17;287(34):28378-85. doi: 10.1074/jbc.M111.312884. Epub 2012 Jul 5.
Adipokines such as adiponectin and visfatin/pre-B-cell colony-enhancing factor (PBEF) have been recently shown to contribute to synovial inflammation in rheumatoid arthritis (RA). In this study, we evaluated the pathophysiological implication of visfatin/PBEF in the molecular patterns of RA synovial tissue, focusing on RA synovial fibroblasts (RASFs), key players in RA synovium. Expression of visfatin/PBEF in synovial fluid and tissue of RA patients was detected by immunoassays and immunohistochemistry. RASFs were stimulated with different concentrations of visfatin/PBEF over varying time intervals, and changes in gene expression were evaluated at the RNA and protein levels using Affymetrix array, real-time PCR, and immunoassays. The signaling pathways involved were identified. The influence of visfatin/PBEF on fibroblast motility and migration was analyzed. In RA synovium, visfatin/PBEF was predominantly expressed in the lining layer, lymphoid aggregates, and interstitial vessels. In RASFs, visfatin/PBEF induced high amounts of chemokines such as IL-8 and MCP-1, proinflammatory cytokines such as IL-6, and matrix metalloproteinases such as MMP-3. Phosphorylation of p38 MAPK was observed after visfatin/PBEF stimulation, and inhibition of p38 MAPK showed strong reduction of visfatin-induced effects. Directed as well as general fibroblast motility was increased by visfatin/PBEF-induced factors. The results of this study indicate that visfatin/PBEF is involved in synovial fibroblast activation by triggering fibroblast motility and promoting cytokine synthesis at central sites in RA synovium.
脂联素和内脏脂肪素/前 B 细胞集落增强因子（PBEF）等脂肪因子最近被证明有助于类风湿关节炎（RA）的滑膜炎症。在这项研究中，我们评估了内脏脂肪素/PBEF 在 RA 滑膜组织分子模式中的病理生理意义，重点关注 RA 滑膜成纤维细胞（RASFs），这是 RA 滑膜中的关键细胞。通过免疫测定法和免疫组织化学法检测 RA 患者滑膜液和组织中的内脏脂肪素/PBEF 表达。用不同浓度的内脏脂肪素/PBEF 刺激 RASFs 不同时间间隔，并在 RNA 和蛋白质水平上使用 Affymetrix 芯片、实时 PCR 和免疫测定法评估基因表达变化。鉴定了涉及的信号通路。分析了内脏脂肪素/PBEF 对成纤维细胞运动和迁移的影响。在 RA 滑膜中，内脏脂肪素/PBEF 主要在衬里层、淋巴聚集物和间质血管中表达。在 RASFs 中，内脏脂肪素/PBEF 诱导大量趋化因子，如 IL-8 和 MCP-1、促炎细胞因子，如 IL-6 和基质金属蛋白酶，如 MMP-3。刺激内脏脂肪素/PBEF 后观察到 p38 MAPK 的磷酸化，抑制 p38 MAPK 显示出对内脏脂肪素诱导作用的强烈抑制。定向和一般成纤维细胞运动都被内脏脂肪素/PBEF 诱导的因子增加。这项研究的结果表明，内脏脂肪素/PBEF 通过触发成纤维细胞运动并促进 RA 滑膜中央部位细胞因子的合成，参与滑膜成纤维细胞的激活。
