Abstract
Paraoxonase 1 (PON1) is an antioxidant enzyme which plays a central role in various diseases. However, the mechanism and function of PON1 protein in inflammation are poorly understood. Since PON1 protein alone cannot be delivered into cells, we generated a cell permeable PEP-1-PON1 protein using protein transduction domains, and examined whether it can protect against cell death in lipopolysaccharide (LPS) or hydrogen peroxide (H2O2)-treated Raw 264.7 cells as well as mice with 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced skin inflammation. We demonstrated that PEP-1-PON1 protein transduced into Raw 264.7 cells and markedly protected against LPS or H2O2-induced cell death by inhibiting cellular reactive oxygen species (ROS) levels, the inflammatory mediator's expression, activation of mitogen-activated protein kinases (MAPKs) and cellular apoptosis. Furthermore, topically applied PEP-1-PON1 protein ameliorates TPA-treated mice skin inflammation via a reduction of inflammatory response. Our results indicate that PEP-1-PON1 protein plays a key role in inflammation and oxidative stress in vitro and in vivo. Therefore, we suggest that PEP-1-PON1 protein may provide a potential protein therapy against oxidative stress and inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Butyrolactone / analogs & derivatives*
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4-Butyrolactone / pharmacology
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Cell Line
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Cell Survival
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Cyclooxygenase 2 / metabolism
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Cytokines / metabolism
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Dermatitis, Contact / immunology
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Dermatitis, Contact / metabolism*
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Disease Models, Animal
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Lipopolysaccharides / pharmacology
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MAP Kinase Signaling System
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Macrophages / immunology*
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred ICR
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NF-kappa B / metabolism
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Oxidative Stress
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Reactive Oxygen Species / metabolism
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Tetradecanoylphorbol Acetate
Substances
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Anti-Inflammatory Agents
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Cytokines
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Lipopolysaccharides
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NF-kappa B
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Reactive Oxygen Species
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Tetradecanoylphorbol Acetate
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4-Butyrolactone
Grants and funding
This work was supported by a Priority Research Centers Program grant (2009-0093812) and in part by a Mid-Career Researcher Program grant (2012R1A2A2A06043084) through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning in the Republic Korea, and in part by a grant of the Korean Health Technology R&D Project (A120960), Ministry of Health & Welfare, Republic of Korea. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.