Abstract
To assess the significance of the non-genomic signaling of TCDD (=dioxin) on liver of C57BL/6 mice and HepG2 human hepatoma cells, we first determined the group of markers that are susceptible to inhibition by parthenolide, a compound known to specifically suppress NF-κB-mediated inflammation. Of those, the most consistent marker turned out to be SOCS3 (a suppressor of cytokine signaling) known to respond to inflammation. An early diagnostic test on the action of TCDD on HepG2 cells in vitro within 3–6 h indicated that Cox-2 and SOCS3 are mainly induced via a non-genomic route, whereas PAI-2 appears to be induced through the classical action route. More detailed diagnostic tests at later stages of action of TCDD in HepG2 cells revealed that induction of IL-1β, BAFF, and iNOS are largely mediated by the protein kinase-dependent non-genomic route. An in vivo study on the 7 day action of TCDD on liver of AhRNLS mice showed that several early markers (e.g., Cox-2, MCP-1 and SOCS3) are induced, but not late markers such as IL-1β. Together, these results show that the non-genomic pathway contributes significantly to the early stress response reactions to TCDD that includes inflammation in hepatoma cells as well as in the liver.
Evaluation of an In vitro Approach to the Prediction of In vivo Effects on Multidrug Resistance in Human Hepatoma Cells
