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.
Highlights
The retinal pigment epithelium (RPE), a single layer of cells located in the posterior part of the eye between the photoreceptors and vascularized choroid, is an indispensable part of the visual system and is responsible for several essential physiological functions
ARPE-19 cells were treated for the specified time with or without various concentrations (0.1, 1, 2 ng/mL) of IL-1β, to explore whether the production of intercellular adhesion molecule-1 (ICAM-1), soluble ICAM-1 (sICAM-1), IL-6, IL-8 and MCP increased after this stimulation
Our results showed that the levels of ICAM-1, sICAM-1, IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in IL-1β-stimulated ARPE-19 cells were positively correlated with the IL-1β concentration and the duration of stimulation, suggesting that these cytokines and chemokines play a crucial part in the process of RPE inflammation
Summary
The retinal pigment epithelium (RPE), a single layer of cells located in the posterior part of the eye between the photoreceptors and vascularized choroid, is an indispensable part of the visual system and is responsible for several essential physiological functions. When RPE cells are stimulated with inflammatory mediators such as tumor necrosis factor (TNF)-α, interferon-γ and interleukin-1β (IL-1β), they will produce cytokines and chemokines and trigger inflammatory responses. RPE cells are crucial elements in the pathogenesis of inflammation-associated progressive eye diseases, of which age-related macular degeneration (AMD) is the most important [4]. Because of the elevated levels of inflammatory cytokines and chemokines such as IL-6, IL-8, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), either locally in the ocular fluids or tissue or systemically in the serum of AMD patients, chronic inflammation is thought to facilitate the progress of AMD [9,10,11,12,13]
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