Mechanisms Involved in the Immunotoxicity Induced by Dermal Application of JP-8 Jet Fuel

Abstract

Dermal application of JP-8 jet fuel induces immune suppression. Classic delayed-type hypersensitivity as well as the induction of contact hypersensitivity to allergens applied to the shaved skin of JP-8-treated mice is suppressed. In addition, the ability of T cells isolated from JP-8-treated mice to proliferate in vitro is suppressed. Here we focused on further characterizing the immunotoxicity induced by JP-8 exposure and determining the mechanism involved. Suppression of T-cell proliferation was first noted 3 to 4 days after a single JP-8 treatment and lasted for approximately 3 weeks, at which time T-cell proliferation returned to normal. Cellular immune reactions appear to be more susceptible to the immunosuppressive effects of JP-8, as antibody production in JP-8-treated mice was identical to that found in normal controls. The mechanism through which dermal application of JP-8 suppresses cell-mediated immune reactions appears to be via the release of immune biological-response modifiers. Blocking the production of prostaglandin E(2) with a selective cyclooxygenase-2 inhibitor abrogated JP-8-induced immune suppression. Neutralizing the activity of interleukin-10 with a highly specific monoclonal antibody also blocked JP-8-induced immune suppression. Furthermore, injecting JP-8-treated mice with recombinant interleukin-12, a cytokine that drives cell-mediated immune reactions in vivo, overcame the immunotoxic effects of JP-8 and restored immune function. These data indicate that immune suppressive cytokines, presumably produced by JP-8-treated epidermal cells, are responsible for immune suppression in JP-8-treated mice and that blocking and/or neutralizing their production in vivo overcomes the immunotoxic effects of JP-8.

A Role for Inflammatory Mediators in the Induction of Immunoregulatory B Cells

“…A good example is the induction of immune suppression that results after dermal exposure to volatile organic chemicals. We find that Th1-type immune reactions are suppressed following dermal application of jet fuel (55,56), and that injecting PAFR antagonists into jet fuel-treated mice blocks the induction of immune suppression (12). It is not clear whether mechanisms similar to those described here are involved, but these observations do suggest that the role of inflammatory mediators in activating immune suppression may be widespread.…”

IL-6 deficiency exacerbates skin inflammation in a murine model of irritant dermatitis

“…Aside from monocytes, the latter cell types tend to be involved in chronic or hypersensitivity reactions and are not generally observed in simple irritant dermatitis such as that induced by JP-8 (Gallucci et al, 2004). Furthermore, it is well known that JP-8 inhibits acquired immune responses (Ullrich and Lyons, 2000;Ramos et al, 2002Ramos et al, , 2007. CXC chemokines can be classified based on receptor specificity as either relatively strict neutrophil chemoattractants (CXCR1 or 2) or lymphocyte chemoattractants (CXCR3), wherein CXCR1/2 is associated with acute inflammation and PMN chemotaxis, and CXCR3 is associated with chronic inflammation (for review, see Baggiolini et al, 1998).…”

Platelet-Activating Factor Is Crucial in Psoralen and Ultraviolet A-Induced Immune Suppression, Inflammation, and Apoptosis

“…18 We also know from previous work that application of other dermal immunotoxic agents, such as jet fuel induces immune suppression via a PAF-, COX-2-, and IL-10-dependent mechanism. 19,20 Many PUVA-induced effects (including immune suppression) may be attributable to the generation of PAF and/or PAF-like molecules by degradation of PC by reactive oxygen species. 9 For instance, phospholipase-A2, a key enzyme in PAF production, can be induced by UVB exposure 8 and possibly also by PUVA.…”