Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation.
Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation.
复制标题
DOI：
10.1016/j.taap.2015.06.017
复制
发表时间：
2015-09-15
影响因子：
3.8
通讯作者：
Ahmed S
中科院分区：
文献类型：
--
作者：
Umar S;Hedaya O;Singh AK;Ahmed S
肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）是由单核/巨噬细胞产生的一种促炎细胞因子，在类风湿关节炎（rheumatoid arthritis，RA）中起重要的病理作用。在这项研究中，我们研究了百里醌（TQ），一种在黑种草中发现的植物化学物质，在调节TNF-α诱导的RA滑膜成纤维细胞（RA-FLS）激活的作用。TQ（1-5 μM）处理对人RA-FLS的活力无明显影响。TQ预处理可抑制TNF-α诱导的RA-FLS中IL-6和IL-8的产生以及ICAM-1、VCAM-1和钙粘蛋白-11（Cad-11）的表达（p<0.01）。TQ抑制TNF-α诱导的RA-FLS中磷酸化p38和磷酸化JNK的表达，但对NF-κB通路无抑制作用（p<0.05; n=4）。有趣的是，我们观察到TQ选择性下调TNF-α诱导的磷酸化p38和磷酸化JNK激活是通过抑制凋亡调节信号激酶1（ASK 1）引起的。TNF-α可选择性地诱导RA-FLS中ASK 1的Thr 845位点磷酸化，TQ预处理可抑制ASK 1的磷酸化，并呈剂量依赖性（p<0.01）。用ASK 1抑制剂（TC ASK 10）预处理RA-FLS，可阻断TNF-α诱导的ICAM-1、VCAM-1和Cad-11的表达。提示TNF-α诱导的ASK 1-p38/JNK通路是RA FLS和TQ细胞因子合成和粘附分子表达增强的重要介质，选择性抑制该通路可能对调节RA的组织破坏具有潜在的治疗价值。
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine produced by monocytes/macrophage that plays a pathological role in rheumatoid arthritis (RA). In this study, we investigate the effect of thymoquinone (TQ), a phytochemical found in Nigella sativa, in regulating TNF-α-induced RA synovial fibroblast (RA-FLS) activation. Treatment with TQ (1–5 μM) had no marked effect on the viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-α-induced interleukin-6 (IL-6) and IL-8 production and ICAM-1, VCAM-1, and cadherin-11 (Cad-11) expression in RA-FLS (p<0.01). Evaluation of the signaling events showed that TQ inhibited TNF-α-induced phospho-p38 and phospho-JNK expression, but had no inhibitory effect on NF-κB pathway, in RA-FLS (p<0.05; n=4). Interestingly, we observed that selective down-regulation of TNF-α-induced phospho-p38 and phospho-JNK activation by TQ is elicited through inhibition of apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-α selectively induced phosphorylation of ASK1 at Thr845 residue in RA-FLS, which was inhibited by TQ pretreatment in a dose dependent manner (p<0.01). Pre-treatment of RA-FLS with ASK1 inhibitor (TC ASK10), blocked TNF-α induced expression of ICAM-1, VCAM-1, and Cad-11. Our results suggest that TNF-α-induced ASK1-p38/JNK pathway is an important mediator of cytokine synthesis and enhanced expression of adhesion molecule in RA-FLS and TQ, by selectively inhibiting this pathway, may have a potential therapeutic value in regulating tissue destruction observed in RA.