ToxSci Advance Access published online on December 18, 2008
Toxicological Sciences, 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
1 To whom correspondence should be addressed: Stephen E. Ullrich, PhD, Department of Immunology-902, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd. Houston, Texas 77030. Fax: 713 563-3280, Telephone: 713 563-3264, E-mail: sullrich{at}mdanderson.org
Received October 21, 2008; revision received December 10, 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 up-regulation 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 NF-
β, which regulates the activity of COX-2, we asked if JP-8-induced ROS and NF-β contributes to COX-2 up-regulation 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 over-expressing catalase or superoxide dismutase genes. JP-8-induced COX-2 expression was also reduced to background in the catalase and superoxide dismutase 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 up-regulation 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.
Current address: Laboratorio de Parsitología, Universidad Autonoma de Yucatan, Merida, Yucatan, Mexico
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