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      Amphiregulin Induces iNOS and COX-2 Expression through NF- κB and MAPK Signaling in Hepatic Inflammation


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          Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, in vivo and in vitro.


          AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF- κB) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting.


          Proinflammatory cytokines (interleukin (IL)-6, IL-1 β, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1 β and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF- κB and MAPKs signaling, and together with NF- κB and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2.


          AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF- κB and MAPKs signaling.

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          Most cited references42

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          NF-κB signaling in inflammation

          The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
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            Mechanisms of NAFLD development and therapeutic strategies

            There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.
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              The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.


                Author and article information

                Mediators Inflamm
                Mediators Inflamm
                Mediators of Inflammation
                11 October 2023
                : 2023
                : 2364121
                1Department of Endocrinology and Metabolism, Ajou University School of Medicine, 206, World cup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea
                2Institute of Medical Science, Ajou University School of Medicine, Suwon, Republic of Korea
                3Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
                Author notes

                Academic Editor: Tomasz Brzozowski

                Author information
                Copyright © 2023 Yu Jung Heo et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 7 April 2023
                : 9 August 2023
                : 16 September 2023
                Funded by: Ministry of Science, ICT and Future Planning
                Award ID: 2023R1A2C1004833
                Award ID: NRF2021M3H1A104892211
                Research Article



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