Resveratrol alleviates inflammatory injury and enhances the apoptosis of fibroblast-like synoviocytes via mitochondrial dysfunction and ER stress in rats with adjuvant arthritis

摘要

Resveratrol, a bioactive compound predominantly found in grapes and red wine, provides a wide range of properties that are beneficial for health, including anticancer and anti-inflammatory activities. Previously published studies have addressed the potential therapeutic effects of resveratrol on rheumatoid arthritis (RA); however, the subcellular mechanism remains to be fully elucidated. In the present study, the therapeutic effects of resveratrol on adjuvant arthritis (AA) in Sprague-Dawley rats were investigated, and the mechanisms of resveratrol-induced apoptosis in fibroblast-like synoviocytes (FLSs) were further examined. Based on the findings, resveratrol treatment over a 12-day period led to a reduction in paw swelling and arthritis scores at the macroscopic level, and an attenuation of inflammatory cell infiltration and synovial hyperplasia, upon a histopathological examination of the AA rats. Furthermore, the administration of resveratrol triggered decreases in the expression of interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) and an increase in the expression of IL-10, alleviating inflammatory injury in AA rats in a dose-dependent manner. In addition, resveratrol was revealed to induce the apoptosis of FLSs when administered with 5 µM H2O2 as determined by elevated levels of Bax, caspase-3, caspase-12 and C/EBP-homologous protein, and the downregulation of B-cell lymphoma 2 (Bcl-2), suggesting that resveratrol is able to induce apoptosis in FLSs via the mitochondrial pathway and endoplasmic reticulum (ER) stress in a milieu containing 5 µM H2O2. Furthermore, JC-1 was used as a fluorescent probe to detect the mitochondrial membrane potential (Δψm), and resveratrol was shown to reduce the Δψm in FLSs in the presence of 5 µM H2O2. However, resveratrol was not able to trigger intracellular calcium overload, although it did suppress ATP- and thapsigargin-induced calcium release from the ER. In conclusion, the present study revealed that resveratrol was able to alleviate inflammatory injury in AA rats, triggering the apoptosis of FLSs via the mitochondrial pathway and ER stress. These results provide a theoretical basis for future treatments using resveratrol for RA.