Abstract
Oxidative stress and inflammation are two interrelated biological events implicated in the pathogenesis of many diseases. Reactive oxygen species (ROS) produced under oxidative stress play a key role in pathological conditions. Inhibition of p22phox, an indispensable component of the NADPH oxidase (NOX) complex comprising the main source of ROS, plays a protective role in many ocular conditions by inhibiting the activation of NOXs and the generation of ROS. However, little is understood regarding the role of p22phox in oxidative stress-related inflammation in the eye. We used a p22phox small interfering RNA (siRNA) to transfect the retinal pigment epithelium (RPE)-derived cell line ARPE-19, and human primary RPE (hRPE) cells, then stimulated with Ang II. We observed a potent anti-inflammatory effect and studied the underlying mechanism. Downregulating p22phox resulted in decreased ROS generation, a reduction of NOXs (NOX1, 2, 4) and a decrease in inflammatory cytokine. In addition, p22phox downregulation reduced the activation of the MAPK and NF-κB signaling pathways. We conclude that inhibition of p22phox has an anti-inflammatory effect in Ang II-induced oxidative stress. Suppressing the MAPK and NF-κB pathways is involved in this protective effect. These results suggest that p22phox may provide a promising therapeutic target for oxidative stress-induced ocular inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / pharmacology*
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Cell Line
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Chemokine CCL2 / antagonists & inhibitors
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Gene Expression Regulation
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Humans
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Inflammation
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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NADPH Oxidase 1
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidases / antagonists & inhibitors*
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Oxidative Stress
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Primary Cell Culture
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RNA, Small Interfering / genetics*
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RNA, Small Interfering / metabolism
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Retinal Pigment Epithelium / cytology
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Retinal Pigment Epithelium / drug effects
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Retinal Pigment Epithelium / metabolism
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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CCL2 protein, human
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Chemokine CCL2
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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Membrane Glycoproteins
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NF-kappa B
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RNA, Small Interfering
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Angiotensin II
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CYBB protein, human
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NADPH Oxidase 1
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidases
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NOX1 protein, human
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NOX4 protein, human
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CYBA protein, human
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases