Effectiveness of the soluble form of the interleukin-1 receptor accessory protein as an inhibitor of. interleukin-1 in collagen-induced arthritis
Effectiveness of the soluble form of the interleukin-1 receptor accessory protein as an inhibitor of. interleukin-1 in collagen-induced arthritis
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DOI：
10.1002/art.11234
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发表时间：
2003-10-01
影响因子：
--
通讯作者：
van den Berg, WB
中科院分区：
文献类型：
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作者：
Smeets, RL;van de Loo, FAJ;van den Berg, WB
Objective.目的探讨可溶性白细胞介素-1（IL-1）受体辅助蛋白（sIL-1 RAcP）在体外是否能特异性抑制IL-1信号通路，并评价其在胶原诱导性关节炎（CIA）中的应用价值。从小鼠肝脏互补DNA中克隆可溶性IL-1 RAcP，并通过使用针对sIL-1 RAcP的腺病毒载体（AdRGD）或稳定转染的NIH 3 T3成纤维细胞系表达可溶性IL-1 RAcP。在NF-κ B荧光素酶报告基因成纤维细胞上测试亲和纯化的sIL-1 RAcP抑制IL-1信号传导的能力，并通过光度计定量。为了研究治疗效果，在胶原免疫的雄性DBA/1小鼠中局部（膝关节）和全身过度表达sIL-1 RAcP。肉眼观察关节炎的严重程度，组织学检查关节的病理过程。从小鼠获得血清以定量IL-6和抗牛11型胶原（BCII）抗体水平。用纯化的sIL-1 RAcP蛋白孵育NF-κ B报告成纤维细胞显示IL-1诱导的NF-κ B活化显著减少，但肿瘤坏死因子诱导的NF-κ B活化没有减少。这表明sIL-1 RAcP作为IL-1信号传导的特异性抑制剂具有新的作用。在CIA发病前将产生sIL-1 RAcP的NIH 3 T3成纤维细胞局部移植到膝关节对这些小鼠的一般疾病严重程度几乎没有影响。接受sIL-1 RAcP细胞移植的膝关节的组织学评价显示关节炎症和骨软骨侵蚀均显著减少。局部治疗sIL-1 RAcP对血清IL-6和抗BCII抗体水平没有显著影响，这表明远端关节持续存在关节炎。与局部治疗相比，全身应用AdRGD治疗sIL-1 RAcP可明显改善CIA。在这项研究中，我们证明了sIL-1 RAcP是一种具有生物活性和创新性的IL-1抑制剂，用sIL-1 RAcP治疗小鼠对胶原诱导的关节炎具有深远的预防作用。
Objective. To investigate whether the soluble form of interleukin-1 (IL-1) receptor accessory protein (sIL-1RAcP), whose physiologic function remains to be established, can serve as a specific inhibitor of IL-1 signaling in vitro, and to evaluate its applicability in collagen-induced arthritis (CIA).Methods. Soluble IL-1RAcP was cloned from murine liver complementary DNA and expressed by the use of either an adenoviral vector (AdRGD) for sIL-1RAcP or a stable-transfected NIH3T3 fibroblast cell line. The ability of affinity-purified sIL-1RAcP to inhibit IL-1 signaling was tested on NF-kappaB luciferase reporter fibroblasts and quantified by luminometer. To investigate therapeutic efficacy, sIL-1RAcP was both locally (knee joint) and systemically overexpressed in collagen-immunized male DBA/1 mice. Severity of arthritis was monitored visually, and the pathologic process in the joint was examined histologically. Serum was obtained from mice to quantify IL-6 and anti-bovine type 11 collagen (BCII) antibody levels.Results. Incubation of the NF-kappaB reporter fibroblast with purified sIL-1RAcP protein showed a marked reduction of IL-1-induced, but not tumor necrosis factor-induced, NF-kappaB activation. This showed a novel role for sIL-1RAcP as a specific inhibitor of IL-1 signaling. Local transplantation of sIL-1RAcP-producing NIH3T3 fibroblasts into the knee before onset of CIA had little or no effect on general disease severity in these mice. Histologic evaluation of the knee joints receiving sIL-1RAcP cell transplantation showed a marked reduction in both joint inflammation and bone and cartilage erosion. Local treatment with sIL-1RAcP had no profound effect on serum levels of IL-6 and anti-BCII antibodies, which is indicative of the ongoing presence of arthritis in distal joints. In contrast to local treatment, systemic treatment with the AdRGD for sIL-1RAcP markedly ameliorated CIA in all joints.Conclusion. In this study we demonstrated that sIL-1RAcP is a biologically active and innovative inhibitor of IL-1, and treatment of mice with sIL-1RAcP had a profound prophylactic effect on collagen-induced arthritis.