ACCELERATED COMMUNICATION Aspects of Dioxin Toxicity Are Mediated by Interleukin 1-Like Cytokines

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) results in a broad spectrum of toxic effects. Most, if not all, of these responses are dependent upon the binding of dioxin to the aryl hydrocarbon receptor. Given their common roles in chemically induced toxicity, we asked whether interleukin 1 (IL1)-like cytokines play a role in acute aspects of the dioxin response. To test this idea, we employed a “triple-null” mouse model that lacks the two receptors for the tumor necrosis factorsand and the receptor for the IL1and IL1cytokines. When triple null mice were treated with dioxin, there was significant attenuation in the levels of serum alanine aminotransferase, signifying reduced hepatocellular damage. In addition, the triple-null mice were protected from dioxin-induced liver inflammation. Loss of receptors for the IL1-like cytokines was not protective for all aspects of dioxin toxicity. Endpoints such as thymic involution, Cyp1a2 induction, hepatomegaly, and hydropic degeneration remain unchanged in this model. The environmental pollutant 2,3,7,8-tetrachlorodibenzo-pdioxin (dioxin) causes a wide spectrum of toxic effects, including hepatocellular damage, thymic involution, teratogenesis, and cancer (Pohjanvirta and Tuomisto, 1994). The aryl hydrocarbon receptor (AHR), a member of the PAS superfamily of transcriptional regulators, mediates most, if not all, of these effects (Poland and Glover, 1980; Schmidt and Bradfield, 1996; Carver et al., 1998). The binding of dioxin to the AHR results in translocation of the receptor complex to the nucleus, where the receptor dimerizes with another basic helix-loop-helix PAS protein known as AHR nuclear translocator (ARNT) (Schmidt and Bradfield, 1996). In the nucleus, the AHR-ARNT heterodimer binds to genomic “dioxin-response elements” (DREs) and up-regulates genes encoding a battery of enzymes, including the cytochrome P450-dependent monooxygenases Cyp1a1, Cyp1a2, and Cyp1b1 (Schmidt and Bradfield, 1996). The induction of these enzymes by the AHR is often referred to as an adaptive response because many AHR agonists, such as benzo(a)pyrene, both induce this pathway and are metabolized through this response (Gu