Abstract
Previous studies in different strains of rats and mice have shown that the inhibition of gluconeogenesis as a result of reduced liver phosphoenolpyruvate carboxykinase (PEPCK) activity together with appetite suppression play critical roles in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent immunological studies in rats demonstrated that exposure to low doses of TCDD resulted in an early and enhanced IgG response to immunization with sheep red blood cells (SRBC) and an enhanced delayed-type hypersensitivity (DTH) reaction as well as a positive popliteal lymph node (PLN) response. However, high doses of TCDD suppressed the DTH reaction. This study aimed at examining the involvement of cytokines (IL-1 and TNF) in mediating the above effects. Liver samples from a previous dose-response study on DTH reaction were investigated, in which rats were treated with TCDD (1, 3, 10, 30 and 90 μg/kg) and immunized with an antigen. mRNA levels of IL-1β were elevated begining at the 1 μg/kg (non-lethal) dosage group with a maximum increase of about 5-fold above controls in the 90 μg/kg (lethal) dosage group. mRNA levels of TNFα were also significantly elevated begining at the 30 μg/kg dosage group. These results suggest that at low doses of TCDD, increased IL-1β could be responsible for immune function stimulation, whereas at high doses of TCDD, greatly elevated TNFα and IL-1β levies may exacerbate or mediate acute toxicity including immune suppression and related biochemical effects. A time course study (60 μg TCDD/kg without immunization) revealed that liver mRNA levels of TNFα were significantly elevated starting 24 h, and reaching a maximum 48 h after dosing with TCDD. This change was accompanied by a transient increase of mRNA levels of IL-1β at day 4 after TCDD dosage. Thus, these data demonstrated that TCDD alone (without immunization) can cause transient increases of mRNA levels of TNFα and IL-1β in liver. Results from these experiments suggest that TCDD-induced cytokine changes may play important roles in various effects of TCDD.
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