Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice.
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 AhR(NLS) 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.
Li
Wen
W
Department of Environmental Toxicology and Center for Health and the Environment, University of California, One Shields Avenue, Davis, CA 95616, USA.
Vogel
Christoph F A
CF
Wu
Dalei
D
Matsumura
Fumio
F
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D015894:Genome, Human; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; D053583:Interleukin-1beta; D017396:Plasminogen Activator Inhibitor 2; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator