Red wine polyphenol extract efficiently protects intestinal epithelial cells from inflammation via opposite modulation of JAK/STAT and Nrf2 pathways

Abstract

The development of therapeutic approaches combining efficacy and safety represents an important goal in intestinal inflammation research. Recently, evidence has supported dietary polyphenols as useful tools in the treatment and prevention of chronic inflammatory diseases, but the mechanisms of action are still poorly understood. We here reveal molecular mechanisms underlying the anti-inflammatory action of a non-alcoholic polyphenol red wine extract (RWE), operating at complementary levels via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and Nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways. RWE significantly reduced the nuclear levels of phosphorylated STAT1 and also the cellular levels of phosphorylated JAK1 induced by cytokines, suppressing the JAK/STAT inflammatory signalling cascade. In turn, RWE increased the Nrf2 nuclear level, activating the Nrf2 pathway, leading not only to an up-regulation of the heme oxygenase-1 (HO-1) expression but also to an increase of the glutamate–cysteine ligase subunit catalytic (GCLc) gene expression, enhancing the GSH synthesis, thereby counteracting GSH depletion that occurs under inflammatory conditions. Overall, data indicate that the anti-inflammatory action of RWE is exerted at complementary levels, via suppression of the JAK/STAT inflammatory pathway and positive modulation of the activity of Nrf2. These results point to the potential use of the RWE as an efficient, readily available and inexpensive therapeutic strategy in the context of gastrointestinal inflammation.