Interleukin-21 Induces Proliferation and Proinflammatory Cytokine Profile of Fibroblast-like Synoviocytes of Patients with Rheumatoid Arthritis
Interleukin-21 Induces Proliferation and Proinflammatory Cytokine Profile of Fibroblast-like Synoviocytes of Patients with Rheumatoid Arthritis
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Interleukin-21 诱导类风湿关节炎患者成纤维样滑膜细胞的增殖和促炎细胞因子谱
DOI：
10.1111/sji.12396
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发表时间：
2016-01-01
影响因子：
3.7
通讯作者：
Liu, X.
中科院分区：
文献类型：
--
作者：
Xing, R.;Yang, L.;Liu, X.
成纤维细胞样滑膜细胞（Fibroblast-like synoviocytes，FLS）通过侵袭性增殖在类风湿关节炎（rheumatoid arthritis，RA）的发病机制中起着关键作用，某些促炎细胞因子可能影响滑膜细胞的增殖。为探讨白细胞介素-21（IL-21）是否能促进RA FLS的增殖和促炎细胞因子的产生，采用免疫组织化学和免疫印迹法观察了RA和骨关节炎（OA）患者滑膜组织和FLS中IL-21受体（IL-21 R）的表达。MTS试验用于分析RA-FLS增殖。通过酶联免疫吸附测定（ELISA）测定培养上清液中IL-6和肿瘤坏死因子-α（TNF-α）的浓度。通过免疫印迹表征由IL-21触发的信号传导途径。与OA患者相比，RA患者的滑膜组织和FLS中IL-21 R上调。IL-21刺激RA-FLS增殖并促进TNF-α和IL-6的产生，并且用IL-21R.Fc阻断IL-21/IL-21 R途径减弱IL-21诱导的增殖和TNF-α和IL-6的分泌。此外，IL-21诱导ERK 1/2、PI 3 K/AKT和STAT 3通路的活化，并且阻断这些通路减弱IL-21诱导的增殖和TNF-α和IL-6的分泌。提示IL-21可促进RA-FLS增殖和促炎细胞因子的产生。因此，针对IL-21的治疗策略可能是治疗RA的有效方法。
Fibroblast-like synoviocytes (FLS) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) through aggressive proliferation and invasion, and certain proinflammatory cytokines may affect synoviocyte proliferation. To evaluate whether interleukin-21 (IL-21) could promote proliferation and proinflammatory cytokine production by RA-FLS, immunohistochemistry and immunoblotting were performed to observe the expression of IL-21 receptor (IL-21R) in synovial tissues and FLS from RA and osteoarthritis (OA) patients. The MTS assay was used to analyse RA-FLS proliferation. The concentrations of IL-6 and tumour necrosis factor-alpha (TNF-alpha) in culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The signalling pathways triggered by IL-21 were characterized by immunoblotting. IL-21R was upregulated in the synovial tissues and FLS of RA patients as compared with OA patients. IL-21 stimulated RA-FLS proliferation and promoted the production of TNF- and IL-6 and blockade of IL-21/IL-21R pathway with IL-21R.Fc attenuated IL-21-induced proliferation and secretion of TNF-alpha and IL-6. Moreover, IL-21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL-21-induced proliferation and secretion of TNF-alpha and IL-6. These results suggest that IL-21 could promote RA-FLS proliferation and production of proinflammatory cytokines. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA.