Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1β signaling and a poor clinical response
Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1β signaling and a poor clinical response
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DOI：
10.1007/s00296-011-1854-6
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发表时间：
2012-05-01
影响因子：
4
通讯作者：
Minota, Seiji
中科院分区：
文献类型：
--
作者：
Matsuyama, Yasushi;Okazaki, Hitoaki;Minota, Seiji
尽管肿瘤坏死因子抑制剂极大地改善了类风湿性关节炎患者的预后，但30%-40%的患者对它们的反应不佳，治疗需要改变。为了区分好的和差的应答者，我们重点研究了用肿瘤坏死因子抑制剂治疗前后血清和滑液中白介素33水平的变化。同时检测了17例肿瘤坏死因子抑制剂阳性患者的滑液和6例患者滑膜成纤维细胞(FLS)，并与多种促炎细胞因子进行了相关性分析。有效组治疗后6个月血清IL-33水平显著下降，而无应答组则无明显变化。6例接受肿瘤坏死因子抑制剂治疗的患者滑液中IL-33水平持续升高，其中3例为难治组，2例中度有效组为轻度升高，1例缓解组为阴性。在17例患者关节液中检测的炎性细胞因子中，IL-33水平仅与IL-1β水平呈显著正相关。IL-1β在体外可显著增加FLS中IL-33的表达，与肿瘤坏死因子-α相比。IL-1β可能通过在肿瘤坏死因子抑制因子-低反应者体内产生促炎因子IL-33而诱导RA炎症。血清和/或滑膜IL-33水平的持续升高可能是对肿瘤坏死因子抑制剂反应差的原因，尽管肿瘤坏死因子抑制剂如何影响IL-33水平仍有待阐明。
Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-na < ve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-na < ve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1 beta. IL-1 beta increased IL-33 expression markedly in FLS in vitro, compared to TNF-alpha. IL-1 beta might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.