Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany.
Exp Mol Pathol. 2012 Feb;92(1):90-6. doi: 10.1016/j.yexmp.2011.10.006. Epub 2011 Oct 19.
Chemerin stimulates migration of leukocytes to sites of inflammation and also increases inflammatory signaling in chondrocytes suggesting a function of chemerin in joint inflammation. Synovial fibroblasts (SF) are critically involved in synovitis and subsequent cartilage destruction. Here, we analyzed whether synovial fibroblasts express chemerin and its receptor CMKLR1. Further, the role of chemerin in synovial fibroblast chemotaxis, proliferation, insulin response and release of inflammatory proteins was studied.
Synovial tissue sections were labeled with chemerin antibody and chemerin was measured in synovial fluid by ELISA. Chemerin mRNA and protein as well as CMKLR1 expression were determined in SFs from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Effects of chemerin on cytokines, chemokines and matrix metalloproteinases (MMP), and on proliferation, migration and insulin signaling were analyzed appropriately.
SFs expressed CMKLR1 and chemerin mRNA, and chemerin protein was found in cell supernatants of synovial fibroblasts. Immunohistochemistry detected chemerin in synovial tissue predominantly localized within the lining layer. Chemerin was present in synovial fluids of RA, OA and psoriatic arthritis patients in similar concentrations. Chemerin neither increased IL-6 levels nor MMP-2 or -9 activity in SFs. Also, it did not act as a chemoattractant for these cells. With respect to intracellular signaling, neither basal nor insulin-mediated phosphorylation of Akt was affected. However, chemerin significantly increased TLR4 mRNA and synthesis of CCL2 in SFs while CCL4 and -5 were not altered. Cell proliferation of SFs, however, was modestly reduced by chemerin.
These data show that human SFs express both chemerin and its receptor. As chemerin enhanced expression of TLR4 and induced release of CCL2 in SFs, a role of this protein in innate immune system-associated joint inflammation is proposed.
趋化素可刺激白细胞迁移至炎症部位，并增加软骨细胞中的炎症信号，提示其在关节炎症中具有功能。滑膜成纤维细胞（SF）在滑膜炎及随后的软骨破坏中起着至关重要的作用。在此，我们分析了滑膜成纤维细胞是否表达趋化素及其受体 CMKLR1。此外，还研究了趋化素在滑膜成纤维细胞趋化性、增殖、胰岛素反应和炎症蛋白释放中的作用。
用趋化素抗体对滑膜组织切片进行标记，并通过 ELISA 法测量滑液中的趋化素。测定骨关节炎（OA）和类风湿关节炎（RA）患者 SF 中的趋化素 mRNA 和蛋白以及 CMKLR1 表达。适当分析趋化素对细胞因子、趋化因子和基质金属蛋白酶（MMP）的影响，以及对增殖、迁移和胰岛素信号的影响。
SF 表达 CMKLR1 和趋化素 mRNA，且细胞上清液中存在趋化素蛋白。免疫组织化学检测到趋化素主要位于滑膜组织衬里层内。RA、OA 和银屑病关节炎患者的滑液中均存在趋化素，浓度相似。趋化素既不会增加 SF 中的 IL-6 水平，也不会增加 MMP-2 或 -9 活性。此外，它也不是这些细胞的趋化剂。就细胞内信号而言，无论是基础状态还是胰岛素介导的 Akt 磷酸化均不受影响。然而，趋化素显著增加了 SF 中的 TLR4 mRNA 和 CCL2 的合成，而 CCL4 和 -5 没有改变。然而，趋化素可适度降低 SF 的细胞增殖。
这些数据表明，人 SF 表达趋化素及其受体。由于趋化素增强了 SF 中的 TLR4 表达并诱导 CCL2 的释放，因此提出该蛋白在与固有免疫系统相关的关节炎症中具有作用。
