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      Quercetin Inhibits the Production of IL-1β-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways

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          Abstract

          Quercetin, a bioflavonoid derived from vegetables and fruits, exerts anti-inflammatory effects in various diseases. Our previous study revealed that quercetin could suppress the expression of matrix metalloprotease-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) to achieve anti-inflammatory effects in tumor necrosis factor-α (TNF-α)-stimulated human retinal pigment epithelial (ARPE-19) cells. The present study explored whether quercetin can inhibit the interleukin-1β (IL-1β)-induced production of inflammatory cytokines and chemokines in ARPE-19 cells. Prior to stimulation by IL-1β, ARPE-19 cells were pretreated with quercetin at various concentrations (2.5–20 µM). The results showed that quercetin could dose-dependently decrease the mRNA and protein levels of ICAM-1, IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1). It also attenuated the adherence of the human monocytic leukemia cell line THP-1 to IL-1β-stimulated ARPE-19 cells. We also demonstrated that quercetin inhibited signaling pathways related to the inflammatory process, including phosphorylation of mitogen-activated protein kinases (MAPKs), inhibitor of nuclear factor κ-B kinase (IKK)α/β, c-Jun, cAMP response element-binding protein (CREB), activating transcription factor 2 (ATF2) and nuclear factor (NF)-κB p65, and blocked the translocation of NF-κB p65 into the nucleus. Furthermore, MAPK inhibitors including an extracellular signal-regulated kinase (ERK) 1/2 inhibitor (U0126), a p38 inhibitor (SB202190) and a c-Jun N-terminal kinase (JNK) inhibitor (SP600125) decreased the expression of soluble ICAM-1 (sICAM-1), but not ICAM-1. U0126 and SB202190 could inhibit the expression of IL-6, IL-8 and MCP-1, but SP600125 could not. An NF-κB inhibitor (Bay 11-7082) also reduced the expression of ICAM-1, sICAM-1, IL-6, IL-8 and MCP-1. Taken together, these results provide evidence that quercetin protects ARPE-19 cells from the IL-1β-stimulated increase in ICAM-1, sICAM-1, IL-6, IL-8 and MCP-1 production by blocking the activation of MAPK and NF-κB signaling pathways to ameliorate the inflammatory response.

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          Most cited references 77

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          Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma.

          Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.
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            Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line.

            Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis. Mast cells induce production of pro-inflammatory cytokines with immune regulatory properties. We investigated the effect of quercetin on the expression of pro-inflammatory cytokines in human mast cell line, HMC-1. HMC-1 cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 (PMACI). Quercetin decreased the gene expression and production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 in PMACI-stimulated HMC-1 cells. Quercetin attenuated PMACI-induced activation of NF-kappaB and p38 mitogen-activated protein kinase. Our study provides evidence that quercetin may suitable for the treatment of mast cell-derived allergic inflammatory diseases.
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              Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells.

              Flavonoids may play an important role for adjunct nutritional therapy of chronic intestinal inflammation. In this study, we characterized the molecular mechanisms by which quercetin and its enteric bacterial metabolites, taxifolin, alphitonin, and 3, 4-dihydroxy-phenylacetic acid, inhibit tumor necrosis factor alpha (TNF)-induced proinflammatory gene expression in the murine small intestinal epithelial cell (IEC) line Mode-K as well as in heterozygous TNFDeltaARE/WT mice, a murine model of experimental ileitis. Quercetin inhibited TNF-induced interferon-gamma-inducible protein 10 (IP-10) and macrophage inflammatory protein 2 (MIP-2) gene expression in Mode-K cells with effective inhibitory concentration of 40 and 44 micromol/L, respectively. Interestingly, taxifolin, alphitonin, and 3,4-dihydroxy-phenylacetic acid did not inhibit TNF responses in IEC, suggesting that microbial transformation of quercetin completely abolished its anti-inflammatory effect. At the molecular level, quercetin inhibited Akt phosphorylation but did not inhibit TNF-induced RelA/I-kappaB phosphorylation and IkappaB degradation or TNF-alpha-induced nuclear factor-kappaB transcriptional activity. Most important for understanding the mechanism involved, chromatin immunoprecipitation analysis revealed inhibitory effects of quercetin on phospho-RelA recruitment to the IP-10 and MIP-2 gene promoters. In addition, and consistent with the lack of cAMP response element binding protein (CBP)/p300 recruitment and phosphorylation/acetylation of histone 3 at the promoter binding site, quercetin inhibited histone acetyl transferase activity. The oral application of quercetin to heterozygous TNFDeltaARE/WT mice [10 mg/(d x kg body wt)] significantly inhibited IP-10 and MIP-2 gene expression in primary ileal epithelial cells but did not affect tissue pathology. These studies support an anti-inflammatory effect of quercetin in epithelial cells through mechanisms that inhibit cofactor recruitment at the chromatin of proinflammatory genes.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                17 June 2019
                June 2019
                : 20
                : 12
                Affiliations
                [1 ]Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 33372, Taiwan; kkaren0330@ 123456yahoo.com.tw
                [2 ]Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; jonghwei@ 123456mail.cgu.edu.tw
                [3 ]Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan; wchuang@ 123456mail.cgust.edu.tw
                [4 ]Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
                [5 ]Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
                [6 ]Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 33372, Taiwan
                [7 ]School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
                [8 ]Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou 33305, Taiwan
                [9 ]Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou 33305, Taiwan
                Author notes
                [* ]Correspondence: mzpjih@ 123456gmail.com (Y.-H.W.); jennycheng@ 123456mail.cgust.edu.tw (C.-Y.C.); Tel.: +886-3-3196200 (ext. 2611) (Y.-H.W.); +886-3-2118999 (ext. 5114) (C.-Y.C.)
                Article
                ijms-20-02957
                10.3390/ijms20122957
                6628093
                31212975
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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