Cytokines (IL-1 beta and TNF alpha) in relation to biochemical and immunological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats

Previous studies in different strains of rats and mice have shown that the inhibition of gluconeogenesis as a result 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 mu g/kg) and immunized with an antigen. mRNA levels of IL-1 beta were elevated begining at the 1 mu g/kg (non-lethal) dosage group with a maximum increase of about 5-fold above controls in the 90 mu g/kg (lethal) dosage group. mRNA levels of TNF alpha were also significantly elevated begining al the 30 mu g/kg dosage group. These results suggest that at low doses of TCDD, increased IL-1 beta could be responsible for immune function stimulation, whereas at high doses of TCDD greatly elevated TNF alpha and IL-1 beta levies may exacerbate or mediate acute toxicity including immune suppression and related biochemical effects. A time course study (60 mu g TCDD/kg without immunization) revealed that liver mRNA levels of TNF alpha 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-1 beta at day 4 after TCDD dosage. Thus, these data demonstrated that TCDD alone (without immunization) can cause transient increases of mRNA levels of TNF alpha and IL-1 beta in liver. Results from these experiments suggest that TCDD-induced cytokine changes may play important roles in various effects of TCDD. Copyright (C) 1997 Elsevier Science Ireland Ltd.