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

Abstract

Applying jet fuel (JP-8) to the skin of mice induces immune suppression. JP-8-treated keratinocytes secrete prostaglandin E(2), 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-kappabeta), which regulates the activity of COX-2, we asked if JP-8-induced ROS and NF-kappabeta 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-kappabeta, 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-kappabeta 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-kappabeta, COX-2 upregulation was blocked. These data indicate that ROS and NF-kappabeta are activated by JP-8, and these pathways are involved in COX-2 expression and the induction of immune suppression by jet fuel.

Jet Fuel Kerosene is not Immunosuppressive in Mice or Rats Following Inhalation for 28 Days

“…Further, linoleic acid was found to suppress the mitogen-stimulated proliferative responses of human T lymphocytes and murine T and B lymphocytes (Tezabwala et al, 1995). Finally, in vivo studies in humans demonstrated that increased intake of linoleic acid elevates production of prostaglandin E2 (PGE2) (Kelley, 2001), which is consistent with the effects of dermal JP-8 exposure on ROS and PGE2 production reported by Ramos et al (2004, 2009). Because DCI-4A is present in JP-8 at a 1:66,660 dilution (AFLMA, 2007), the concentration of dilinoleic acid in JP-8 is extremely low.…”

Subacute effects of inhaled Jet Fuel-A (Jet A) on airway and immune function in female rats

“…Studies of dermal application of jet fuel in mice have been interpreted as indicating immune suppression (Ramos et al, 2009;Ullrich, 1999;Ullrich & Lyons, 2000). A dermal study in female Sprague-Dawley rats, however, found jet fuel to lack immunotoxicity.…”

Effect of melilotus extract on lung injury by upregulating the expression of cannabinoid CB2 receptors in septic rats

“…It was shown that through involvement in the transcription of a variety of cytokine genes, NF-κβ could exert a complicated impact on the regulating network. Activated NF-κβ can enhance the transcription of many cytokines, such as TNF-α and IL-1, [ 19 ], to lengthen the synthesizing time and quantity of inflammation factors [ 20 ]. Inhibition of NF-κβ activity can decrease the expression of inflammatory media regulated by NF-κβ, and reduce the infiltration and activation of inflammatory cells, thus protecting lung tissues from damage [ 21 ].…”