Lycopene Inhibits IL-6 Expression by Upregulating NQO1 and HO-1 via Activation of Nrf2 in Ethanol/Lipopolysaccharide-Stimulated Pancreatic Acinar Cells

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.

Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats

“…Bilirubin is an endogenous radical scavenger. 32 GSH, SOD, and CAT constitute the antioxidant defense system in organisms and play a key role in scavenging oxygen-free radicals and peroxides. Moreover, cells and tissues are damaged when the oxidative stress caused by ROS exceeds the body's defenses.…”

“…HO-1 can promote the production of bilirubin. Bilirubin is an endogenous radical scavenger . GSH, SOD, and CAT constitute the antioxidant defense system in organisms and play a key role in scavenging oxygen-free radicals and peroxides.…”

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis — a systematic review

“…Furthermore, our research of literature revealed that Nrf2 signaling was restored by several exogenous antioxidants, such as high-dose vitamin C, pomegranate extract, Tanshinone IIA (the main active component of red sage), and lycopene. However, this effect was abolished when inhibitors of Nrf2 were used (Xu et al 2020;Gupta et al 2019;Chen 2020;Lee et al 2022). Nrf2 pathway may be influenced by several other factors, including melatonin, hepatocyte growth factor, vinpocetine, borneol, visnagin, chitosan oligosaccharides, or flavonoids derived from Coreopsis tinctoria nuts (Jung et al 2010;Palestino-Dominguez et al 2018;Abdelzaher et al 2021;Bansod et al 2021;Pasari 2019;Mei, et al 2021;Du, et al 2018).…”

Oral Lycopene Administration Attenuates Inflammation and Oxidative Stress by Regulating Plasma Lipids in Rats with Lipopolysaccharide-Induced Epididymitis

“… 12 Due to its many conjugated double bonds, LYC shows two and ten times higher singlet oxygen quenching rates than β-carotene and α-tocopherol. 13 , 14 According to the study, LYC reduces ROS and inhibits LPS-induced IL-6 expression in pancreatic acinar cells, preventing the occurrence of alcohol/LPS-related pancreatitis. 14 In another study of LPS-induced uveitis in SD rats, LYC injection significantly reduced inflammatory cell infiltration and the levels of pro-inflammatory cytokines, indicating the inhibitory effect of LYC on inflammation.…”

“… 13 , 14 According to the study, LYC reduces ROS and inhibits LPS-induced IL-6 expression in pancreatic acinar cells, preventing the occurrence of alcohol/LPS-related pancreatitis. 14 In another study of LPS-induced uveitis in SD rats, LYC injection significantly reduced inflammatory cell infiltration and the levels of pro-inflammatory cytokines, indicating the inhibitory effect of LYC on inflammation. 15 In addition, for Escherichia coli-induced chronic bacterial prostatitis, the combination of LYC and ciprofloxacin was superior to ciprofloxacin alone in improving bacterial growth and prostate inflammation.…”