Liver diseases, including viral and autoimmune hepatitis, represent a major public health concern. Inflammatory immune cells play an important role in the development and progression of liver injury in these diseases. There is evidence that exposure to various xenobiotics enhances the response of immune cells to inflammatory stimuli, resulting in exacerbation of hepatic inflammation and development of liver injury. In particular, the persistent environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) represents a serious environmental health concern and has numerous adverse effects in humans and other mammals that include altered immune function. Information on the effects of TCDD on hepatic immune cells following inflammatory stimulus is limited, and the effects of TCDD on development of hepatic autoimmune disease are unknown. Administration of concanavalin A (Con A) to rodents is widely used as a model of immune-mediated liver injury with pathophysiology resembling that of autoimmune hepatitis in humans. In this dissertation I tested the hypothesis that TCDD pretreatment enhances the response of intrahepatic immune cells to the inflammatory stimulus Con A resulting in increased hepatotoxicity in a mouse model of autoimmune liver disease. Mice were pretreated with TCDD, and the development of liver injury after the administration of Con A was assessed. Mice pretreated with TCDD had an increased response to Con A, resulting in severe liver injury mediated by inflammatory cytokines and hepatic innate immune cells. Interferon gamma (IFNγ) was critical to the development of TCDD/Con A-induced liver injury: pretreatment with TCDD increased the plasma concentration of IFNγ after Con A, and IFNγ knockout mice were protected from injury. In addition, pretreatment with TCDD induced activation of hepatic NK and NKT cells after Con A administration. In TCDD-pretreated mice, the percentage of NKT cells expressing Fas ligand was increased after Con A. Further investigation determined that Fas ligand-mediated killing of hepatic parenchymal cells was an important contributor to TCDD/Con A-induced liver injury and mice deficient in Fas ligand were protected from injury. NKT cell-deficient mice were protected against injury from Con A alone, whereas liver injury from TCDD/Con A treatment was only partially reduced suggesting the involvement of other immune cell populations in the exacerbation of Con A-mediated liver injury. Neither hepatic macrophages nor infiltrating neutrophils were involved in the increased sensitivity to Con A-induced liver injury; however, increased activation of NK cells was an important contributor. NK cell depletion prevented the development of liver injury and decreased plasma concentration of IFNγ after TCDD/Con A treatment. These results indicate that TCDD alters the severity and pathogenesis of Con A-mediated liver injury and raise the possibility that exposure to environmental toxicants like TCDD might contribute to the development of hepatic autoimmune disease in humans.
Read
