Abstract
Oxidative stress is a major risk factor for acute pancreatitis. Reactive oxygen species (ROS) mediate expression of inflammatory cytokines such as interleukin-6 (IL-6) which reflects the severity of acute pancreatitis. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is activated to induce the expression of antioxidant enzymes such as NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) as a cytoprotective response to oxidative stress. In addition, binding of Kelch-like ECH-associated protein 1 (Keap1) to Nrf2 promotes degradation of Nrf2. Docosahexaenoic acid (DHA)—an omega-3 fatty acid—exerts anti-inflammatory and antioxidant effects. Oxidized omega-3 fatty acids react with Keap1 to induce Nrf2-regulated gene expression. In this study, we investigated whether DHA reduces ROS levels and inhibits IL-6 expression via Nrf2 signaling in pancreatic acinar (AR42J) cells stimulated with cerulein, as an in vitro model of acute pancreatitis. The cells were pretreated with or without DHA for 1 h and treated with cerulein (10−8 M) for 1 (ROS levels, protein levels of NQO1, HO-1, pNrf2, Nrf2, and Keap1), 6 (IL-6 mRNA expression), and 24 h (IL-6 protein level in the medium). Our results showed that DHA upregulates the expression of NQO1 and HO-1 in cerulein-stimulated AR42J cells by promoting phosphorylation and nuclear translocation of Nrf2. DHA increased interaction between Keap1 and Nrf2 in AR42J cells, which may increase Nrf2 activity by inhibiting Keap1-mediated sequestration of Nrf2. In addition, DHA-induced expression of NQO1 and HO-1 is related to reduction of ROS and IL-6 levels in cerulein-stimulated AR42J cells. In conclusion, DHA inhibits ROS-mediated IL-6 expression by upregulating Nrf2-mediated expression of NQO1 and HO-1 in cerulein-stimulated pancreatic acinar cells. DHA may exert positive modulatory effects on acute pancreatitis by inhibiting oxidative stress and inflammatory cytokine production by activating Nrf2 signaling in pancreatic acinar cells.
Highlights
Acute pancreatitis involves mild and severe inflammatory conditions of the pancreas
Since chronic alcohol abuse promotes generation of reactive oxygen species (ROS) [4] which are responsible for the initiation of the inflammatory process in the pancreatic acinar cells [5], oxidative stress is reported to be involved in the pathogenesis of both acute and chronic pancreatitis
We summarized that Docosahexaenoic acid (DHA) suppressed the expression of inflammatory mediators by inhibiting ROS-mediated activation of PKC-δ, NF-κB, activator protein-1 (AP-1), janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), and inflammatory cytokines in a cerulein-stimulated experimental model for acute pancreatitis [37]
Summary
Acute pancreatitis involves mild and severe inflammatory conditions of the pancreas. The pathogenic mechanisms of acute pancreatitis remain poorly understood, oxidative stress and inflammatory mediators are suggested as major factors in the development of acute pancreatitis [1,2]. Since chronic alcohol abuse promotes generation of reactive oxygen species (ROS) [4] which are responsible for the initiation of the inflammatory process in the pancreatic acinar cells [5], oxidative stress is reported to be involved in the pathogenesis of both acute and chronic pancreatitis. ROS and reactive nitrogen species (RNS) have been implicated in the pathogenesis of acute pancreatitis. ROS and RNS act directly on biomolecules (lipids, proteins, and nucleic acids) and oxidize these components of cell membrane in the pancreas leading to membrane disintegration and necrosis of the pancreatic cells. ROS and RNS can serve as secondary messengers in intracellular signaling and induce pro-inflammatory cascades [6]
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