Resveratrol Protects against TNF-α-Induced Injury in Human Umbilical Endothelial Cells through Promoting Sirtuin-1-Induced Repression of NF-KB and p38 MAPK

Abstract

Inflammation and reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α)-induced injury in human umbilical endothelial cells (HUVECs) using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1); and repression of SIRT1 by small-interfering RNA (siRNA) and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF)-κB inhibitor pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs.

Inhibition of influenza virus via a sesquiterpene fraction isolated from Laggera pterodonta by targeting the NF-κB and p38 pathways

“…NF-κB is also involved in the inflammatory response, inducing the transcription of proinflammatory cytokines, such as TNF-α, IL-6, and IL-8, and the expression of enzymes, such as inducible cyclooxygenase [20, 21]. P38 is also related to the innate immune response, controlling the expression of cytokines such as RANTES, IL-8 and TNF-α [22], and research has demonstrated that p38/MAPK may act as an upstream activator of the NF-κB signalling pathway [23]. Our results indicated that fr 14 inhibited the protein p65/NF-κB and p38/MAPK phosphorylation at concentrations of 50, 100, and 150 μg/ml but did not affect ERK/MAPK.…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…At vascular level, a strong interaction occurs between oxidative stress and activation of redox-sensitive transcription factors, such as nuclear factor-kappa B (NF-jB), leading to the characteristic proinflammatory phenotype by mediating the production of cytokines and prothrombotic markers (11,35,141,565) (Fig. 2).…”

“…SIRT1 interacts with RelA/ p65 protein in the NF-jB complex and deacetylates Lys-310, an effect that correlates with a loss of NF-jB-regulated gene expression (207). Indeed, SIRT1 activators, such as resveratrol and SRT1720, ameliorate cardiac oxidative stress in diabetes, protect ECs against tumor necrosis factora (TNF-a)-induced injury, and reverse vascular endothelial dysfunction by repressing NF-jB transcriptional activity (11,56,141).…”

“…In this regard, reduced levels of SIRT1 lead to an increased acetylation of Lys-310 on the p65 subunit of NF-jB, resulting in an increased inflammatory response in ECs and monocytes/macrophages (11,35,56,141,150,163,207,208).…”

Species difference in reactivity to lignin-like enzymatically polymerized polyphenols on interferon-γ synthesis and involvement of interleukin-2 production in mice

“…For instance, tea polymerized polyphenols can inhibit pancreatic lipase activity [1], and turmeric root curcumin-derivatives can suppress colon cancer development [2]. In the food immunology field, many reports have suggested that low-molecular weight phenolic compounds such as curcumin, epigallocatechin gallate, and resveratrol can suppress the immune system by inhibiting nuclear factor-κB activation [3][4][5]. These low-molecular weight polyphenols have been considered as anti-inflammatory substances and used as alternative medicines for the symptomatic therapy of inflammatory diseases [6,7].…”