Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interleukin-6
Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interleukin-6
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DOI：
10.1080/14397595.2018.1532545
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发表时间：
2019-11-02
影响因子：
2.2
通讯作者：
Sumida, Takayuki
中科院分区：
文献类型：
--
作者：
Kawaguchi, Hoshimi;Matsumoto, Isao;Sumida, Takayuki
目的：通过蛋白精氨酸脱亚胺酶（PAD）抑制肽葡萄糖-6-磷酸异构酶诱导的关节炎（pGIA），探讨瓜氨酸化蛋白与抗瓜氨酸化蛋白抗体（ACPA）的相关性。方法：将PAD抑制剂Cl-amidine注入pGIA。评估临床评分和踝关节组织病理学结果。ELISA法检测血清ACPA滴度。免疫组化和Western blot检测关节和血清中瓜氨酸化蛋白的表达。采用细胞头阵列（CBA）检测血清IL-6、TNF α和IL-1 β水平。定量PCR检测关节、淋巴结、脾脏组织中IL-6、TNF α基因表达水平。评估淋巴结T细胞gpi特异性产生的IFN γ和IL-17。结果：偕胺治疗明显降低关节炎严重程度，ACPA滴度趋于降低，但与对照组相比无显著差异。治疗小鼠关节和血清中的瓜氨酸化蛋白明显减少。cl -脒组大鼠血清IL-6水平显著降低，关节组织IL-6和TNF - α基因表达显著降低。在氯脒处理的小鼠中，gpi特异性T细胞产生的IL-17倾向于降低，但没有显著差异。结论：pad介导的瓜氨酸化蛋白通过IL-6参与了关节炎的发病过程。
Objective: To explore the relevance of citrullinated proteins and anti-citrullinated protein antibodies (ACPA) via protein arginine deiminase (PAD) inhibition in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA).Methods: Cl-amidine, a PAD inhibitor, was injected into pGIA. Clinical scores and histopathological findings of ankle joints were assessed. Serum ACPA titers were analyzed using ELISA. Citrullinated protein expression in joints and sera were examined with immunohistochemistry and Western blot analysis, respectively. Serum levels of IL-6, TNF alpha, and IL-1 beta were measured with cytometric bead array (CBA). Gene expression levels of IL-6 and TNF alpha in joints, lymph nodes, and spleens were analyzed with quantitative PCR. GPI-specific productions of IFN gamma and IL-17 from T cells in lymph nodes were evaluated.Results: Cl-amidine treatment significantly reduced arthritis severity while ACPA titers tended to be lower, but not significantly different compared to the control. Citrullinated proteins in joints and sera from treated mice were clearly decreased. With Cl-amidine treatment, serum IL-6 levels were significantly decreased, and IL-6 and TNF alpha gene expression were significantly reduced in joints. IL-17 production from GPI-specific T cells tended to be lower in Cl-amidine-treated mice, but not significantly different.Conclusion: Our results suggested that PAD-mediated citrullinated protein was involved in the pathogenesis of arthritis via IL-6.