Thymoquinone inhibits TNF-?-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation.

ABSTRACT: Tumor necrosis factor-? (TNF-?) 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-?-induced RA synovial fibroblast (RA-FLS) activation. Treatment with TQ (1-5?M) had no marked effect on the viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-?-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-?-induced phospho-p38 and phospho-JNK expression, but had no inhibitory effect on NF-?B pathway, in RA-FLS (p<0.05; n=4). Interestingly, we observed that selective down-regulation of TNF-?-induced phospho-p38 and phospho-JNK activation by TQ is elicited through inhibition of apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-? 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-? induced expression of ICAM-1, VCAM-1, and Cad-11. Our results suggest that TNF-?-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.

SUBMITTER: Umar S 

PROVIDER: S-EPMC4549173 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature