Inhibition of Interleukin-33 Signaling Attenuates the Severity of Experimental Arthritis
Inhibition of Interleukin-33 Signaling Attenuates the Severity of Experimental Arthritis
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DOI：
10.1002/art.24305
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发表时间：
2009-03-01
影响因子：
--
通讯作者：
Gabay, Cem
中科院分区：
文献类型：
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作者：
Palmer, Gaby;Talabot-Ayer, Dominique;Gabay, Cem
Objective.白细胞介素-33（IL-33;或IL-1F 11）最近被鉴定为IL-1家族受体T1/ST 2的配体。本研究的目的是检测人和小鼠关节中IL-33的产生，并研究IL-33和T1/ST 2在实验性关节炎中的作用。在人滑膜组织、类风湿性关节炎（RA）滑膜成纤维细胞和关节炎小鼠关节中检查IL-33表达。在疾病发作时开始用阻断性抗ST 2抗体或对照抗体治疗患有胶原诱导的关节炎（CIA）的小鼠。通过临床和组织学评分评估关节炎的严重程度。体外检测引流淋巴结（LN）细胞的反应，并使用联合信使RNA（mRNA）进行表达谱分析。IL-33在人RA滑膜组织中高表达。在培养的滑膜成纤维细胞中，IL-1 β和/或肿瘤坏死因子α强烈诱导IL-33表达。此外，在CIA小鼠关节中检测到IL-33 mRNA，并且在疾病的早期阶段增加。在疾病发作时给予阻断性抗ST 2抗体可减轻CIA的严重程度并减少关节破坏。抗-ST 2抗体治疗与干扰素-γ产生的显著减少以及与离体刺激的引流LN细胞产生的IL-17的更有限的减少相关。最后，抗ST 2治疗可降低关节中RANKL mRNA水平。IL-33在发炎的关节中局部产生，并且IL-33信号传导的中和对关节炎的过程具有治疗作用。这些观察结果表明，局部产生的IL-33可能有助于关节炎症和破坏的发病机制。
Objective. Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis.Methods. IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling.Results. IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1 beta and/or tumor necrosis factor a. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment.Conclusion. IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.