p53 Contributes to Quercetin-Induced Apoptosis in Human Rheumatoid Arthritis Fibroblast-like Synoviocytes

Abstract

In the present study, we sought to explore the mechanism of quercetin-induced apoptosis in rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs). DNA fragmentation assay was used to detect quercetin-induced apoptosis in RAFLSs. The cleavages of caspase-3 and caspase-9 and the accumulation of cytosolic cytochrome C were measured by western blot in quercetin-treated RAFLSs. Mitochondrial membrane potential was tested by flow cytometry. Small interfering RNAs were used to knock down the expression of protein 53 (p53) and analyze the role of p53 in quercetin-induced apoptosis in RAFLSs. DNA fragmentation assay showed that quercetin dose-dependently elevated the apoptosis of RAFLSs, accompanying with enhanced caspase-3 and caspase-9 cleavages. Moreover, quercetin caused a concentration-dependent loss of mitochondrial membrane potential and cytochrome c release to cytosol and also decreased Bcl-2/Bax ratio, indicating that quercetin-induced apoptosis is through mitochondrial pathway. Quercetin also elevated p53 phosphorylation at ser15. Pretreatment with pifithrin-α, a p53 inhibitor, significantly diminished p53 phosphorylation at the concentration of 30 μM and abrogated quercetin-induced apoptosis in a dose-dependent manner. Quercetin-induced apoptosis was also significantly blocked by p53 silencing, further suggesting the involvement of p53 in quercetin-induced apoptosis in RAFLSs. Our study indicated that quercetin-induced apoptosis of RAFLSs is through mitochondrial pathway, in which p53 plays an important role.

Therapeutic effect of quercetin in collagen-induced arthritis

“…The antiangiogenic effect of quercetin was also demonstrated in vitro and in vivo experiments using human umbilical vein endothelial cells and chicken chorioallantoic membrane respectively [33]. Additionally, Tan WF et al [33] reported that quercetin inhibited the proliferation of NIH-3T3 fibroblast cells, while studies in RA patients revealed that quercetin induced apoptosis of fibroblast-like synoviocytes (FLS) by activating p53, reducing cytochrome c release and inhibiting Bcl-2, Bax and IL-1 [25,44]. Apoptosis induced by quercetin has also been reported in DC [43].…”

“…[16]. d) prevents angiogenesis; e) inhibits transcription factors such as NF-; f) reduces enzymes like MMPs, COX, hyaluronidases and collagenases; g) promotes apoptosis of pathogenic cells, and h) inhibits oxidative metabolism [21,[25][26][27][28][29][30][31][32][33].…”

Relationship Between Redox Status and Cell Fate in Immunity and Autoimmunity

“…Huang et al (68) demonstrated that quercetin can suppress dendritic cell activation and, thus, may potentially be used for the prevention and treatment of inflammation, autoimmunity, and transplantation. Moreover, quercetin can induce apoptosis in RA fibroblast-like synoviocytes through mitochondrial pathway (188). Evidence for the possible clinical applications of quercetin is increasing.…”

Resveratrol promotes apoptosis and G2/M cell cycle arrest of fibroblast-like synoviocytes in rheumatoid arthritis through regulation of autophagy and the serine-threonine kinase-p53 axis

“…Taken together, all these data suggest that resveratrol could inhibit TNF-α-induced cell proliferation and promote cell apoptosis at least partly through downregulation of Beclin-1, further inhibiting TNF-α-induced autophagy in RA-FLS.p53, a tumour-suppressor protein, plays a central role in the induction of cell cycle arrest and cell apoptosis in response to diverse cellular stimuli. Accumulating evidence has demonstrated that p53 plays a crucial role in RA-FLS cell apoptosis[3,20,32]. p53 signalling pathway has become a promising target in the treatment of RA.…”