<p>Resveratrol Exerts Anti-Osteoarthritic Effect by Inhibiting TLR4/NF-κB Signaling Pathway via the TLR4/Akt/FoxO1 Axis in IL-1β-Stimulated SW1353 Cells</p>

Abstract

Osteoarthritis (OA) is associated with chronic low-grade inflammation. Resveratrol exerts protective effects on OA through its anti-inflammatory property; however, the mechanism of resveratrol on anti-inflammatory signaling pathways has not been fully elucidated yet. The aim of the present study was to investigate whether resveratrol-mediated PI3K/Akt expression is linked to TLR4/NF-κB pathway and the role of TLR4/Akt/FoxO1 axis in the anti-osteoarthritic effect of resveratrol. Methods: SW1353 cells stimulated by IL-1β (10 ng/mL) were cultured in the presence or absence of resveratrol (50 μM) and then treated with TLR4 siRNA, PI3K inhibitor LY294002 or FoxO1 siRNA, respectively. The associated proteins of TLR4 signaling pathways and TLR4/Akt/FoxO1 axis were evaluated by Western blot. The level of IL-6 in the supernatant was detected by ELISA. Results: IL-1β treatment increased the expression of TLR4/NF-κB and phosphorylation of PI3K/Akt and FoxO1, while additional resveratrol further upregulated the expression of PI3K/Akt and FoxO1 phosphorylation but downregulated TLR4 signals in SW1353 cells. Further analyses by the inhibition of TLR4, PI3K/Akt and FoxO1 signaling pathways, respectively, showed that the activation of TLR4 can induce PI3K/Akt phosphorylation, which increases the phosphorylation of FoxO1 and inactivates it. Next, inactivated-FoxO1 can reduce the expression of TLR4, which forms a self-limiting mechanism of inflammation. Resveratrol treatment can upregulate PI3K/Akt phosphorylation and inactivate FoxO1, thereby reducing TLR4 and inflammation. Conclusion: This study reveals that TLR4/Akt/FoxO1 inflammatory self-limiting mechanism may exist in IL-1β-stimulated SW1353 cells. This study reveals a novel cross-talk mechanism which is between integrated PI3K/Akt/FoxO1 signaling network and TLR4driven innate responses in IL-1β-stimulated SW1353 cells. Resveratrol may exert anti-OA effect by enhancing the self-limiting mechanism of inflammation through TLR4/Akt/FoxO1 axis.

Effect of Dietary Polyphenols on Osteoarthritis—Molecular Mechanisms

“…This nutraceutical has many health-benefiting properties, including its anti-inflammatory, antioxidant, and anticancer properties. By modulating major oxidative stress signaling pathways, resveratrol has become one of the most studied nutraceuticals in managing degenerative diseases such as OA [ 51 , 52 , 54 , 55 , 56 , 57 , 67 ] ( Table 1 ).…”

“…In vivo and in vitro studies provided more detailed mechanistic information on the resveratrol’s actions in modulating pain, reducing inflammation, and exerting a protective effect in OA patients [ 51 , 52 , 55 , 57 ]. Its protective effects were demonstrated in an in vivo model where resveratrol ameliorated inflammatory damage in a rat OA model [ 55 ] through its impact on the NF-κB and HO-1/Nrf-2 signaling pathway [ 52 ]. Resveratrol downregulated the expression of TNF-α, IL-1β, IL-6, and IL-18 and the caspase-3/9 activity.…”

The Antioxidant Resveratrol Protects against Chondrocyte Apoptosis by Regulating the COX-2/NF-κB Pathway in Created Temporomandibular Osteoarthritis

“…And our study verified the therapeutic effect of RES on MCC cells by flow cytometry, which demonstrated that RES significantly reversed IL-1 β -induced apoptosis in the chondrocytes. Some studies verified that RES exerted protective effects on OA through its anti-inflammatory property by the NF- κ B pathway [ 25 , 26 ]. The present study agreed with previous studies, which revealed the anti-inflammation of RES on TMJOA by inhibiting the COX-2 gene expression, NF- κ B pathway, and downstream factors MMPs.…”

The mechanism of nicotinamide on reducing acute lung injury by inhibiting MAPK and NF-κB signal pathway

“…Our study found that NAM could effectively reduce the accumulation of IL-6 in the lung, and the cell experiments also showed that NAM could inhibit the expression of IL-6 by macrophages. IL-1β can activate Toll-like receptors in macrophages (Xu et al 2020 ), thus exacerbating the inflammatory response (Gabay et al 2010 ). Our research showed that NAM could reduce the expression of IL-1β in the lung, and we also found that NAM could inhibit the gene expression of IL-1β in macrophages.…”