Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis
Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis
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DOI：
10.1002/art.20218
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Distler, O
中科院分区：
文献类型：
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作者：
Jüngel, A;Distler, JHW;Distler, O
目标。目的探讨细胞因子/受体对白细胞介素-21 (IL-21)/IL-21受体（IL-21R）在类风湿关节炎（RA）中的作用及表达。采用TaqMan实时聚合酶链式反应（PCR）和原位杂交技术分析RA和骨关节炎（OA）患者滑膜活检标本中IL-21R和IL-21的表达。抗cd68抗体原位杂交后免疫组化双标记。Western blotting证实IL-21R在蛋白水平的表达。用重组il -1 β、肿瘤坏死因子α (TNFalpha)、血小板衍生生长因子（PDGF）和转化生长因子β (tgf β)进行刺激实验。分析IL-21R在SCID小鼠ra共着床模型中软骨破坏中的作用。IL-21R在RA患者的总RNA提取物和滑膜活检样本中被发现，而在OA患者的样本中没有表达或只有少量表达。双标记显示滑膜巨噬细胞和滑膜成纤维细胞均表达IL-21R。抗IL-21R抗体Western blotting证实IL-21R蛋白在RA滑膜成纤维细胞（rasf）中表达。值得注意的是，在体内和体外相同的样品中，real-time PCR和原位杂交无法检测到IL-21。IL-21R信使RNA （mRNA）的表达水平不受il -1 β、TNFalpha、PDGF或tgfβ的刺激而改变。有趣的是，在SCID小鼠共植入模型中，rasf在入侵软骨部位没有维持IL-21R的表达。同样，IL-21R mRNA在RA滑膜软骨和骨浸润部位无表达。我们的数据表明，IL-21R在RA滑膜中通过rasf和滑膜巨噬细胞表达。IL-21R与rasf的活化表型相关，独立于主要的促炎细胞因子il -1 β和TNFalpha，但与关节软骨和骨的破坏呈负相关。
Objective. To determine the role and expression of the cytokine/receptor pair interleukin-21 (IL-21)/IL-21 receptor (IL-21R) in rheumatoid arthritis (RA).Methods. The expression of IL-21R and IL-21 was analyzed by TaqMan real-time polymerase chain reaction (PCR) and in situ hybridization of synovial biopsy samples from patients with RA and osteoarthritis (OA). Double labeling by immunohistochemistry after in situ hybridization was performed with anti-CD68 antibodies. The expression of IL-21R at the protein level was confirmed by Western blotting. Stimulation experiments were performed with recombinant IL-1beta, tumor necrosis factor alpha (TNFalpha), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGFbeta). The role of IL-21R in cartilage destruction was analyzed in the SCID mouse coimplantation model of RA.Results. IL-21R was found in total RNA extracts and in synovial biopsy samples from RA patients, whereas no expression or only minimal expression was seen in samples from OA patients. Double labeling indicated that both synovial macrophages and synovial fibroblasts expressed IL-21R. Western blotting with anti-IL-21R antibodies confirmed the expression of IL-21R protein in RA synovial fibroblasts (RASFs). Of note, IL-21 was not detectable by real-time PCR and in situ hybridization in the same samples in vivo as in vitro. The level of expression of IL-21R messenger RNA (mRNA) was not altered by stimulation with IL-1beta, TNFalpha, PDGF, or TGFbeta. Interestingly, in the SCID mouse coimplantation model, RASFs did not maintain their expression of IL-21R at sites of invasion into the cartilage. Similarly, IL-21R mRNA was not expressed at sites of invasion into cartilage and bone in RA synovium.Conclusion. Our data demonstrate that IL-21R is expressed in RA synovium by RASFs and synovial inacrophages. IL-21R is associated with the activated phenotype of RASFs independently of the major proinflammatory cytokines IL-1beta and TNFalpha, but correlates negatively with the destruction of articular cartilage and bone.