The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics

Abstract

Dietary oxysterols are cholesterol auto-oxidation products widely present in cholesterol-rich foods.They are thought to affect the intestinal barrier function, playing a role in gut inflammation. This study has characterized specific cell signals that are up-regulated in differentiated CaCo-2 colonic epithelial cells by a mixture of oxysterols representative of a hyper-cholesterolemic diet. p38 MAPK activation plays a major role, while other signal branches, i.e. the JNK and ERK pathways, make minor contributions to the intestinal inflammation induced by dietary oxysterols. p38 transduction might be the missing link connecting the known NADPH oxidase activation, and the induction of NF-κB-dependent inflammatory events related to oxysterols' action in the intestine. A NOX1/p38 MAPK/NF-κB signaling axis was demonstrated by the quenched inflammation observed on blocking individual branches of this signal with specific chemical inhibitors. Further, all these signaling sites were prevented when CaCo-2 cell were pre-incubated with phenolic compounds extracted from selected wines made of typical Sardinian grape varieties: red Cannonau and white Vermentino. Notably, Cannonau was more effective than Vermentino. The effect of Sardinian wine extracts on intestinal inflammation induced by dietary oxysterols might mainly be due to their phenolic content, more abundant in Cannonau than in Vermentino. Furthermore, among different phenolic components of both wines, epicatechin and caffeic acid exerted the strongest effects. These findings show a major role of the NOX1/p38 MAPK/NF-κB signaling axis in the activation of oxysteroldependent intestinal inflammation, and confirm the concept that phenolics act as modulators at different sites of pro-oxidant and pro-inflammatory cell signals.

Lipid Oxidation Products in the Pathogenesis of Inflammation-related Gut Diseases

“…The evidence that an oxysterol mixture stemming from the heating of dietary cholesterol exerts pro-inflammatory effects on human CaCo-2 enterocytes is in accordance with the hypothesis of a possible key role of oxysterols even in bowel inflammation; among the oxysterols present in the mixture, 7-OH was the most effective [83]. In these cells the oxysterol-induced inflammation was confirmed to be mediated by NF-B-MAPK signaling pathways [84]. Conversely, a previous study showed that 25-OH but not 7-OH significantly enhanced IL-8 mRNA expression and synthesis in CaCo-2 cells stimulated with IL-1 [85].…”

“…For example, increased ROS levels leading to mitochondrial perturbation and apoptosis were reported for CaCo-2 cells exposed to 7-OH [93]. In the same cells the observed interleukin over-expression and apoptotic response appeared to be triggered by oxysterols through NOX1 activation and consequent intracellular ROS steady-state increase [83,84,91,92].…”

“…NOX1 and p38 MAPK activities have been shown to be negatively regulated by specific polyphenols present in wine. The down-stream transcriptional factor mainly involved in the cellular regulation by polyphenols appears to be NF-B [84]. Polyphenols also show prebiotic activity by inhibiting the growth of detrimental bacteria and stimulating beneficial bacteria such as Lactobacteria and Bifidobacteria in the gut [128,129].…”

Argan Oil-Mediated Attenuation of Organelle Dysfunction, Oxidative Stress and Cell Death Induced by 7-Ketocholesterol in Murine Oligodendrocytes 158N

“…These results were revealed by phase-contrast microscopy and the crystal violet and MTT test. As observed with α- and γ-tocopherol [ 35 ], docosahexahenoic acid [ 60 ], oleic acid [ 35 ], polyphenols [ 94 , 95 , 96 , 97 ] and dimethylfumarate [ 58 ], argan oil was also able to markedly reduce oxidative stress, evaluated as the percentage of cells overproducing superoxide anions revealed by staining with DHE, and the percentage of cells permeable to PI, which can correspond to dead cells and/or to cells with damaged plasma membranes, as a consequence, at least in part, of lipid peroxidation and of the disorganization of the lipid membrane occurring as a result of treatment with 7KC [ 54 , 98 ]. The cytoprotective effect of argan oil on the plasma membrane is in agreement with previous data from studies on retinal pigment epithelial (RPE) cells, which showed that argan oil is incorporated into retinal cells and increased plasma membrane fluidity [ 99 ].…”

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

“…In human retinal pigment epithelial cells (ARPE-19), resveratrol (a polyphenol mainly found in red wine) showed cytoprotective effects and was able to inhibit VEGF-secretion [44]. Polyphenolic extracts of wine (epicatechin, epigallocatechin-3-gallate, caffeic acid) also prevent inflammation induced by a mixture of oxysterols representative of a hyper-cholesterolemic diet in CaCo-2 colonic epithelial cells [45,46]. Indicaxanthin, a bioactive pigment from cactus pear fruit, has also been shown to prevent 7KC-induced cell death in different cell types [47,48,49].…”