Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan.
Affiliated Hospital of Jining Medical University, Jining.
Clin Exp Immunol. 2018 Apr;192(1):82-94. doi: 10.1111/cei.13080. Epub 2017 Dec 21.
The thioredoxin domain-containing 5 (TXNDC5) gene is associated with susceptibility to rheumatoid arthritis (RA) and exhibits increased expression in the synovial tissues. TXNDC5 is also associated strongly with diabetes, a metabolic disease characterized by interrupted insulin signalling. This study investigated whether TXNDC5 contributes to RA via the insulin signalling pathway. In this study, RA synovial fibroblast-like cells (RASFs) transfected with an anti-TXNDC5 small interfering RNA (siRNA) were analysed with an insulin signaling pathway RT profiler polymerase chain reaction (PCR) array and an insulin resistance RT profiler PCR array. The PCR arrays detected significantly increased expression of insulin-like growth factor binding protein 1 (IGFBP1) in RASFs with suppressed TXNDC5 expression. The result was verified using real-time PCR and Western blot analyses. Significantly elevated IGFBP1 expression and decreased interleukin (IL)-6 secretion were also detected in culture medium of transfected RASFs. Furthermore, decreased IGFBP1 mRNA and protein expression levels were detected in RA synovial tissues. Additionally, significantly increased apoptosis and decreased cell proliferation and cell migration were observed in RASFs transfected with the anti-TXNDC5 siRNA, whereas transfection with the anti-IGFBP1 siRNA or a mixture of the anti-IGFBP1 and anti-TXNDC5 siRNAs restored normal cell proliferation, migration and IL-6 level in RASFs. Insulin-like growth factor (IGF) has potent prosurvival and anti-apoptotic functions, and IGFBP1 can suppress IGF activity. Based on the results of the present study, we suggest that TXNDC5 contributes to abnormal RASF proliferation, migration and IL-6 production by inhibiting IGFBP1 expression.
硫氧还蛋白结构域包含 5（TXNDC5）基因与类风湿关节炎（RA）的易感性相关，并且在滑膜组织中表达增加。TXNDC5 还与代谢疾病糖尿病密切相关，糖尿病的特征是胰岛素信号中断。本研究探讨了 TXNDC5 是否通过胰岛素信号通路导致 RA。在这项研究中，用抗-TXNDC5 小干扰 RNA（siRNA）转染 RA 滑膜成纤维样细胞（RASFs），并用胰岛素信号通路 RT 探针聚合酶链反应（PCR）阵列和胰岛素抵抗 RT 探针 PCR 阵列进行分析。PCR 阵列检测到 TXNDC5 表达受抑制的 RASFs 中胰岛素样生长因子结合蛋白 1（IGFBP1）的表达显著增加。使用实时 PCR 和 Western blot 分析验证了该结果。转染的 RASFs 培养基中还检测到 IGFBP1 表达显著升高和白细胞介素（IL）-6 分泌减少。此外，在 RA 滑膜组织中也检测到 IGFBP1 mRNA 和蛋白表达水平降低。此外，用抗-TXNDC5 siRNA 转染的 RASFs 中观察到凋亡增加，细胞增殖和细胞迁移减少，而用抗-IGFBP1 siRNA 或抗-IGFBP1 和抗-TXNDC5 siRNA 的混合物转染则恢复了 RASFs 的正常细胞增殖、迁移和 IL-6 水平。胰岛素样生长因子（IGF）具有强大的促生存和抗凋亡功能，而 IGFBP1 可以抑制 IGF 活性。基于本研究的结果，我们认为 TXNDC5 通过抑制 IGFBP1 表达导致 RASF 增殖、迁移和 IL-6 产生异常。
