Abstract
In alcoholic pancreatitis, alcohol increases gut permeability, which increases the penetration of endotoxins, such as lipopolysaccharides (LPS). LPS act as clinically significant triggers to increase pancreatic damage in alcoholic pancreatitis. Ethanol or LPS treatment increases reactive oxygen species (ROS) production in pancreatic acinar cells. ROS induce inflammatory cytokine production in pancreatic acinar cells, leading to pancreatic inflammation. The nuclear erythroid-2-related factor 2 (Nrf2) pathway is activated as a cytoprotective response to oxidative stress, and induces the expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). Lycopene exerts anti-inflammatory and antioxidant effects in various cells. We previously showed that lycopene inhibits NADPH oxidase to reduce ROS and IL-6 levels, and zymogene activation in ethanol or palmitoleic acid-treated pancreatic acinar cells. In this study, we examined whether lycopene inhibits IL-6 expression by activating the Nrf2/NQO1-HO-1 pathway, and reducing intracellular and mitochondrial ROS levels, in ethanol and LPS-treated pancreatic AR42J cells. Lycopene increased the phosphorylated and nuclear-translocated Nrf2 levels by decreasing the amount of Nrf2 sequestered in the cytoplasm via a complex formation with Kelch-like ECH1-associated protein 1 (Keap1). Using exogenous inhibitors targeting Nrf2 and HO-1, we showed that the upregulation of activated Nrf2 and HO-1 results in lycopene-induced suppression of IL-6 expression and ROS production. The consumption of lycopene-rich foods may prevent the development of ethanol and LPS-associated pancreatic inflammation by activating Nrf2-mediated expression of NQO1 and HO-1, thereby decreasing ROS-mediated IL-6 expression in pancreatic acinar cells.
Highlights
Publisher’s Note: MDPI stays neutralExcessive alcohol consumption is associated with pancreatic damage, including pancreatitis and pathological inflammation of the pancreas
We previously showed that lycopene reduced reactive oxygen species (ROS) levels, and inhibited nuclear factor-κB (NF-κB) activation and the expression of IL-6, in cerulein-stimulated pancreatic acinar cells [28]
As the activity of nuclear erythroid-2-related factor 2 (Nrf2) is inhibited by Kelch-like ECH-associated protein 1 (Keap1) through protein–protein interactions, we examined whether lycopene changes the interaction between Keap1 and Nrf2 in AR42J
Summary
Excessive alcohol consumption is associated with pancreatic damage, including pancreatitis and pathological inflammation of the pancreas. Alcohol-induced oxidative stress is linked to ethanol (EtOH) metabolism in the pancreas [1]. The pancreas metabolizes EtOH via both oxidative and non-oxidative pathways. The oxidative pathway involves the enzymes alcohol dehydrogenase and cytochrome P4502E1 (CYP2E1); these enzymes convert. Of EtOH metabolism at physiological alcohol concentrations [2–4]. EtOH-induced increases in reactive oxygen species (ROS) generation and lipid peroxidation have been shown to be blocked by inhibitors of CYP2E1 and anti-CYP2E1 immunoglobulin G [5]. The nonoxidative pathway involves the formation of an ester linkage between EtOH and fatty acids, which is mediated by fatty acid ethyl ester (FAEE) synthases. An increase in FAEE levels has been noted in the pancreas of rats and humans following alcohol consumption [6,7]
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