Resveratrol decreases the expression of genes involved in inflammation through transcriptional regulation

Abstract

Oxidative stress generated during inflammation is associated with a wide range of pathologies. Resveratrol (RESV) displays anti-inflammatory and antioxidant activities, being a candidate for the development of adjuvant therapies for several inflammatory diseases. Despite this potential, the cellular responses induced by RESV are not well known. In this work, transcriptomic analysis was performed following lipopolysaccharide (LPS) stimulation of monocyte cultures in the presence of RESV. Induction of an inflammatory response was observed after LPS treatment and the addition of RESV led to decreases in expression of the inflammatory mediators, tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), without cytotoxicity. RNA sequencing revealed 823 upregulated and 2098 downregulated genes (cutoff ≥2.0 or ≤−2.0) after RESV treatment. Gene ontology analysis showed that the upregulated genes were associated with metabolic processes and the cell cycle, consistent with normal cell growth and differentiation under an inflammatory stimulus. The downregulated genes were associated with inflammatory responses, gene expression, and protein modification. The prediction of master regulators using the iRegulon tool showed nuclear respiratory factor 1 (NRF1) and GA-binding protein alpha subunit (GABPA) as the main regulators of the downregulated genes. Using immunoprecipitation and protein expression assays, we observed that RESV was able to decrease protein acetylation patterns, such as acetylated apurinic/apyrimidinic endonuclease-1/reduction-oxidation factor 1 (APE1/Ref-1), and increase histone methylation. In addition, reductions in p65 (nuclear factor-kappa B (NF-κB) subunit) and lysine-specific histone demethylase-1 (LSD1) expression were observed. In conclusion, our data indicate that treatment with RESV caused significant changes in protein acetylation and methylation patterns, suggesting the induction of deacetylase and reduction of demethylase activities that mainly affect regulatory cascades mediated by NF-кB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. NRF1 and GABPA seem to be the main regulators of the transcriptional profile observed after RESV treatment.

Anti-Inflammatory Action and Mechanisms of Resveratrol

“…In addition, resveratrol treatment improved neuroimmune dysregulation via inhibiting pro-inflammatory mediators and TLRs/NF-κB pathway [68]. In a recent study conducted by Lopes Pinheiro et al [38], resveratrol treatment initiated substantial changes in protein acetylation and methylation patterns, indicating deacetylase induction and demethylase reduction activities that primarily affect regulatory cascades NF-кB-and JAK/STAT-mediated pathway. In summary, NF-κB is a molecular target for the treatment of inflammatory diseases.…”

“…Lipopolysaccharides (LPS) is an essential glycolipid component of Gram-negative bacterial endotoxin which can trigger inflammatory responses to the host [36]. The addition of resveratrol has also led to decreases in inflammatory mediator expression, including prostaglandin (PG)E2, COX-2, IL-1β, IL-8, TNF-α, and monocyte chemoattractant protein-1 in BV-2 or monocyte LPS stimulation cells [37,38]. Additionally, Toll-like receptor-4 (TLR-4) expression in LPS-stimulated cells was attenuated after resveratrol pre-treatment [39].…”

Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

“…Resveratrol could also inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling independent of SIRT1 [40]. Moreover, resveratrol attenuated inflammation by downregulating high mobility group box 1 (HMGB1) as well as suppressing NF-κB and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways [41,42]. In addition, both in vitro and in vivo, the anti-inflammatory effects of resveratrol were associated with its inhibition of the toll-like receptor 4 (TLR4)/NF-κB signaling cascade [43,44].…”

Health benefits of resveratrol administration

“…Resveratrol suppresses IL-6 transcription and translation, resulting in attenuation of its secretion by macrophages (Ohtsu et al, 2017). Likewise, the administration of resveratrol to monocyte cultures leads to a reduction in the expression of inflammatory mediators: TNF-α and IL-8, without inducing cytotoxicity (Pinheiro et al, 2018).…”