2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury
| Autor: | Robert A. Roth, Patricia E. Ganey, Aaron M. Fullerton |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Fas Ligand Protein Polychlorinated Dibenzodioxins Time Factors chemical and pharmacologic phenomena Inflammation Biology Toxicology Article Fas ligand Proinflammatory cytokine Interferon-gamma Mice Immune system Internal medicine Concanavalin A medicine Animals heterocyclic compounds Interferon gamma reproductive and urinary physiology Mice Knockout Pharmacology Liver injury Dose-Response Relationship Drug medicine.disease Natural killer T cell Mice Inbred C57BL Disease Models Animal stomatognathic diseases Endocrinology Gene Expression Regulation Cytokines Natural Killer T-Cells Environmental Pollutants Chemical and Drug Induced Liver Injury medicine.symptom Cell activation medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 266:317-327 |
| ISSN: | 0041-008X |
| Popis: | Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four. Mice treated with TCDD did not develop liver injury; however, TCDD pretreatment increased liver injury resulting from moderate doses of Con A (4–10 mg/kg). TCDD-pretreated mice had altered plasma concentrations of inflammatory cytokines, including interferon gamma (IFNγ), and TCDD/Con A-induced hepatotoxicity was attenuated in IFNγ knockout mice. At various times after treatment, intrahepatic immune cells were isolated, and expression of cell activation markers as well as cytolytic proteins was determined. TCDD pretreatment increased the proportion of activated natural killer T (NKT) cells and the percent of cells expressing Fas ligand (FasL) after Con A administration. In addition FasL knockout mice and mice treated with CD18 antiserum were both protected from TCDD/Con A-induced hepatotoxicity, suggesting a requirement for direct cell–cell interaction between effector immune cells and parenchymal cell targets in the development of liver injury from TCDD/Con A treatment. In summary, exposure to TCDD increased NKT cell activation and exacerbated immune-mediated liver injury induced by Con A through a mechanism involving IFNγ and FasL expression. |
| Databáze: | OpenAIRE |
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