Journal Article

JP-8 Induces Immune Suppression via a Reactive Oxygen Species NF-κβ–Dependent Mechanism

Gerardo Ramos, Alberto Y. Limon-Flores and Stephen E. Ullrich

in Toxicological Sciences

Volume 108, issue 1, pages 100-109
Published in print March 2009 | ISSN: 1096-6080
Published online December 2008 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfn262
JP-8 Induces Immune Suppression via a Reactive Oxygen Species NF-κβ–Dependent Mechanism

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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-κβ), which regulates the activity of COX-2, we asked if JP-8–induced ROS and NF-κβ 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-κβ, 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-κβ 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-κβ, COX-2 upregulation was blocked. These data indicate that ROS and NF-κβ are activated by JP-8, and these pathways are involved in COX-2 expression and the induction of immune suppression by jet fuel.

Keywords: cutaneous; cytokines; siRNA; volatile organic compounds

Journal Article.  7174 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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