Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol)

A single oral exposure to the trichothecene vomitoxin (VT) has been previou sly shown in the mouse to increase splenic mRNA levels for several cytokine s in as little as 2 h. Since one underlying mechanism for these effects lik ely involves superinduction of transiently expressed cytokine genes,VT may also potentially amplify cytokine responses to inflammatory stimuli. To tes t this possibility, the effects of oral VT exposure on tumor necrosis facto r-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta expression were me asured in mice that were intraperitoneally injected with lipopolysaccharide (LPS), a prototypic inflammatory agent. As anticipated, VT alone at 1, 5, and 25 mg/kg body weight increased splenic mRNA expression of all three cyt okines after 3 h in a dose-response fashion. LPS injection at 1 and 5 mg/kg body weight also induced proinflammatory cytokine mRNA expression. There w as a synergistic increase in TNF-alpha splenic mRNA levels in mice treated with both VT and LPS as compared to mice treated with either toxin alone, w hereas the effects were additive for IL-6 and IL-1 beta mRNA expression. Wh en relative mRNA levels were examined over a 12-h period in mice given LPS (1 mg/kg) and/or VT (5 mg/kg), significant enhancementwas observed up to 6, 12, and 3 h for TNF-alpha, IL-6, and IL-1 beta, respectively. When plasma cytokine concentrations were measured, TNF-alpha was round to peak at I h a nd was significantly increased at 1, 3, and 6 h if mice were given IPS and VT, whereas LPS or VT alone caused much smaller increases in plasma TNF-alp ha. Plasma IL-6 peaked at 3 h in LPS, VT, and LPS/VT groups, with the combi ned toxin group exhibiting additive effects. Plasma IL-lp was not detectabl e. The potential for VT and LPS to enhance toxicity was examined in a subse quent study. Mortality was not observed up to 72 h in mice exposed to a sin gle oral dose or VT at 25 mg/kg body weight or to an intraperitoneal dose o f LPS at 1 or 5 mg/kg body weight; however, all mice receiving VT and eithe r LPS dose became moribund in less than 40 h. The principal histologic lesi ons in the moribund mice treated with VT and IFS were marked cell death and loss in thymus, Peyer's patches, spleen, and bone marrow. In all or these lymphoid tissues, treatment-induced cell death had characteristic histologi c features of apoptosis causing lymphoid atrophy. These results suggest tha t LPS exposure may markedly increase the toxicity of trichothecenes and tha t the immune system was a primary target of these interactive effects.