Frommer Klaus W, Zimmermann Birgit, Meier Florian M P, Schröder Dirk, Heil Matthias, Schäffler Andreas, Büchler Christa, Steinmeyer Jürgen, Brentano Fabia, Gay Steffen, Müller-Ladner Ulf, Neumann Elena
Justus-Liebig-University Giessen and Kerckhoff-Klinik, Bad Nauheim, Germany.
Arthritis Rheum. 2010 Oct;62(10):2886-99. doi: 10.1002/art.27616.
Rheumatoid arthritis (RA) is associated with increased production of adipokines, which are cytokine-like mediators that are produced mainly in adipose tissue but also in synovial cells. Since RA synovial fibroblasts (RASFs), lymphocytes, endothelial cells, and chondrocytes are key players in the pathophysiology of RA, this study was undertaken to analyze the effects of the key adipokine adiponectin on proinflammatory and prodestructive synovial effector cells.
Lymphocytes were activated in part prior to stimulation. All cells were stimulated with adiponectin, and changes in gene and protein expression were determined by Affymetrix and protein arrays. Messenger RNA and protein levels were confirmed using semiquantitative reverse transcription-polymerase chain reaction (PCR), real-time PCR, and immunoassays. Intracellular signal transduction was evaluated using chemical signaling inhibitors.
Adiponectin stimulation of human RASFs predominantly induced the secretion of chemokines, as well as proinflammatory cytokines, prostaglandin synthases, growth factors, and factors of bone metabolism and matrix remodeling. Lymphocytes, endothelial cells, and chondrocytes responded to adiponectin stimulation with enhanced synthesis of cytokines and various chemokines. Additionally, chondrocytes released increased amounts of matrix metalloproteinases. In RASFs, adiponectin-mediated effects were p38 MAPK and protein kinase C dependent.
Our previous findings indicated that adiponectin was present in inflamed synovium, at sites of cartilage invasion, in lymphocyte infiltrates, and in perivascular areas. The findings of the present study indicate that adiponectin induces gene expression and protein synthesis in human RASFs, lymphocytes, endothelial cells, and chondrocytes, supporting the concept of adiponectin being involved in the pathophysiologic modulation of RA effector cells. Adiponectin promotes inflammation through cytokine synthesis, attraction of inflammatory cells to the synovium, and recruitment of prodestructive cells via chemokines, thus promoting matrix destruction at sites of cartilage invasion.
类风湿关节炎（RA）与脂肪因子产生增加有关，脂肪因子是一类细胞因子样介质，主要在脂肪组织中产生，但也可在滑膜细胞中产生。由于RA滑膜成纤维细胞（RASFs）、淋巴细胞、内皮细胞和软骨细胞是RA病理生理学中的关键参与者，因此开展本研究以分析关键脂肪因子脂联素对促炎和促破坏滑膜效应细胞的影响。
淋巴细胞在部分刺激前被激活。所有细胞均用脂联素刺激，基因和蛋白表达的变化通过Affymetrix和蛋白阵列进行测定。使用半定量逆转录聚合酶链反应（PCR）、实时PCR和免疫测定法确认信使核糖核酸和蛋白水平。使用化学信号抑制剂评估细胞内信号转导。
脂联素刺激人RASFs主要诱导趋化因子以及促炎细胞因子、前列腺素合成酶、生长因子以及骨代谢和基质重塑因子的分泌。淋巴细胞、内皮细胞和软骨细胞对脂联素刺激的反应是细胞因子和各种趋化因子的合成增加。此外，软骨细胞释放的基质金属蛋白酶量增加。在RASFs中，脂联素介导的效应依赖于p38丝裂原活化蛋白激酶（MAPK）和蛋白激酶C。
我们之前的研究结果表明，脂联素存在于炎症滑膜、软骨侵袭部位、淋巴细胞浸润处和血管周围区域。本研究结果表明，脂联素诱导人RASFs、淋巴细胞、内皮细胞和软骨细胞中的基因表达和蛋白合成，支持脂联素参与RA效应细胞病理生理调节的概念。脂联素通过细胞因子合成、将炎性细胞吸引至滑膜以及通过趋化因子募集促破坏细胞来促进炎症，从而促进软骨侵袭部位的基质破坏。
