ToxSci Advance Access originally published online on December 18, 2008
Toxicological Sciences 2009 108(1):100-109; doi:10.1093/toxsci/kfn262
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JP-8 Induces Immune Suppression via a Reactive Oxygen Species NF-
β–Dependent Mechanism
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* The Department of Immunology and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
The Toxicology Program, The Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas 77225
2 To whom correspondence should be addressed at Department of Immunology-902, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Fax: (713) 563-3280. E-mail: sullrich{at}mdanderson.org.
Received October 21, 2008; accepted December 11, 2008
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Abstract |
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Applying jet fuel (JP-8) to the skin of mice induces immune suppression. JP-8–treated keratinocytes secrete prostaglandin E2, which is essential for activating immune suppressive pathways. The molecular pathway leading to the upregulation of the enzyme that controls prostaglandin synthesis, cyclooxygenase (COX)-2, is unclear. Because JP-8 activates oxidative stress and because reactive oxygen species (ROS) turn on nuclear factor kappa B (NF-
β), which regulates the activity of COX-2, we asked if JP-8–induced ROS and NF-β contributes to COX-2 upregulation and immune suppression in vivo. JP-8 induced the production of ROS in keratinocytes as measured with the ROS indicator dye, aminophenyl fluorescein. Fluorescence was diminished in JP-8–treated keratinocytes overexpressing catalase or superoxide dismutase (SOD) genes. JP-8–induced COX-2 expression was also reduced to background in the catalase and SOD transfected cells, or in cultures treated with N-acetylcysteine (NAC). When NAC was injected into JP-8–treated mice, dermal COX-2 expression, and JP-8–induced immune suppression was inhibited. Because ROS activates NF-β, we asked if this transcriptional activator played a role in the enhanced COX-2 expression and JP-8–induced immune suppression. When JP-8–treated mice, or JP-8–treated keratinocytes were treated with a selective NF-β inhibitor, parthenolide, COX-2 expression, and immune suppression were abrogated. Similarly, when JP-8–treated keratinocytes were treated with small interfering RNA specific for the p65 subunit of NF-β, COX-2 upregulation was blocked. These data indicate that ROS and NF-β are activated by JP-8, and these pathways are involved in COX-2 expression and the induction of immune suppression by jet fuel.
Key Words: cutaneous; cytokines; siRNA; volatile organic compounds.
1 Present address: Laboratorio de Parsitología, Universidad Autonoma de Yucatan, Merida, Yucatan, Mexico
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