Grape Pomace Extract Attenuates Inflammatory Response in Intestinal Epithelial and Endothelial Cells: Potential Health-Promoting Properties in Bowel Inflammation.

Nadia Calabriso,Marika Massaro,Carmela Gerardi,Tiziano Verri,Maria Annunziata Carluccio,Egeria Scoditti,Giovanna Giovinazzo,Amilcare Barca

doi:10.3390/nu14061175

Abstract

Inflammatory bowel disease (IBD) implies the chronic inflammation of the gastrointestinal tract, combined with systemic vascular manifestations. In IBD, the incidence of cardiovascular disease appears to be related to an increase of oxidative stress and endothelial dysfunction. Grape pomace contains high levels of anti-oxidant polyphenols that are able to counteract chronic inflammatory symptoms. The aim of this study was to determine whether grape pomace polyphenolic extract (GPE) was able to mitigate the overwhelming inflammatory response in enterocyte-like cells and to improve vascular function. Intestinal epithelial Caco-2 cells, grown in monolayers or in co-culture with endothelial cells (Caco-2/HMEC-1), were treated with different concentrations of GPE (1, 5, 10 µg/mL gallic acid equivalents) for 2 h and then stimulated with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α for 16 h. Through multiple assays, the expression of intestinal and endothelial inflammatory mediators, intracellular reactive oxygen species (ROS) levels and NF-κB activation, as well as endothelial-leukocyte adhesion, were evaluated. The results showed that GPE supplementation prevented, in a concentration-dependent manner, the intestinal expression and release of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinases (MMP)-9 and MMP-2. In Caco-2 cells, GPE also suppressed the gene expression of several pro-inflammatory markers, such as IL-1β, TNF-α, macrophage colony-stimulating factor (M-CSF), C-X-C motif ligand (CXCL)-10, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and cyclooxygenase (COX)-2. The GPE anti-inflammatory effect was mediated by the inhibition of NF-κB activity and reduced intracellular ROS levels. Furthermore, transepithelial GPE suppressed the endothelial expression of IL-6, MCP-1, VCAM-1, and ICAM-1 and the subsequent adhesion of leukocytes to the endothelial cells under pro-inflammatory conditions. In conclusion, our findings suggest grape pomace as a natural source of polyphenols with multiple health-promoting properties that could contribute to the mitigation of gut chronic inflammatory diseases and improve vascular endothelial function.

Highlights

Cardiovascular diseases (CVD) represent the main cause of mortality and morbidity worldwide, due to the continuous increase in the prevalence of cardiovascular risk factors
We used a polyphenolic extract from the grape pomace of the Negramaro cv (GPE), by applying an eco-sustainable and safe strategy previously developed by our research group [21]
To verify the mechanisms underlying the reduced release of these proinflammatory molecules, we investigated the effects of grape pomace polyphenolic extract (GPE) on IL-6 and monocyte chemoattractant protein (MCP)-1 gene expression

Summary

Introduction

Cardiovascular diseases (CVD) represent the main cause of mortality and morbidity worldwide, due to the continuous increase in the prevalence of cardiovascular risk factors. Endothelial dysfunction is a systemic disorder characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and pro-inflammatory factors, as well as deficiency of nitric oxide bioavailability [6,7]. In both CVD and IBD, pro-inflammatory angiogenesis is recognized as a common trait, sustaining both atherosclerotic plaque growth and intestinal inflammation [8,9]. IBD patients have a disrupted mucosal barrier, and, as a consequence, proinflammatory and pro-angiogenic products through the gut lining may enter the circulation and directly promote inflammation by activating immune cells and endothelial cells, known triggers in the onset and progression of CVD [11]. The boosted expression of endothelial adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and of chemoattractants, is involved in the recruitment of monocytes/macrophages to endothelial cells, which is an obliged step in atherosclerotic development and progression [14]

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