Effects of TNF-α on autophagy of rheumatoid arthritis fibroblast-like synoviocytes and regulation of the NF-κB signaling pathway
【Abstract】
1. Although autophagy is involved in various forms of cellular stimulation of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA), including the regulation of hunger, hypoxia and inflammation, its mechanism has not been fully elucidated.
2. In this study, we found that TNF-α could activate autophagy in RA-FLSs. When autophagy was blocked by two different mechanisms using autophagy specific blockers (3-MA, CQ), the autophagy level of FLSs was significantly decreased, while the imbalance of proliferation / apoptosis induced by TNF-α was reversed. We also found that PDTC, a specific NF-κB pathway blocker, significantly decreased the production of NF-κB marker protein phosphorylated P65 (p-P65) and the expression of autophagy-related proteins after blocking the pathway activity.
3. In summary, these findings demonstrate for the first time that TNF-α can activate the autophagy of FLSs, that blocking autophagy may up-regulate apoptosis and inhibit cell proliferation, and that the NF-κB pathway may positively regulate autophagy in RA-FLSs.
Rheumatoid arthritis (RA) is a common chronic autoimmune disease, which seriously harms human health. The hyperplastic growth of fibroblast-like synoviocytes (FLSs) plays a key role in the pathogenesis of RA. However, the pathogenesis of RA remains unclear. In this experiment, we confirmed that Tumor necrosis factor alpha (TNF-α) could activate the autophagy of RA-FLSs. 3-Methyladenine (3-MA) and Chloroquine (CQ), two types of autophagy blocker, combined with TNF-α were used to treat FLSs. The results showed that this treatment caused a reduction in the level of autophagy-related protein, significant increases in the expression of apoptosis-related protein and the apoptosis rate, and significant inhibition of the proliferation-promoting ability of TNF-α. Ammonium pyrrolidinedithiocarbamate (PDTC), a specific nuclear factor kappa-B (NF-κB) activity blocker, significantly inhibited autophagy induced by TNF-α. Collectively, these findings showed, for the first time, that TNF-α can up-regulate autophagy activity and activate the NF-κB signal pathway. Inhibition of autophagy can improve the imbalance of proliferation/apoptosis of FLSs aggravated by TNF-α to some extent, thus delaying the progression of RA. The NF-κB signal pathway may be involved in the regulation of FLSs autophagy by TNF-α.
【Author】
YuWang, WeiGao
【Keywords】
rheumatoid arthritis, autophagy, TNF-α, NF-κB 
【Journal】
Immunobiology(IF：2.8) Time：2021-01-24
