Superfund Research Program
Influence of Ah Receptor Ligands on Inflammatory Responses: Consequences for Tissue Injury and Gene Expression
Project Leader: Patricia E. Ganey
Grant Number: P42ES004911
Funding Period: 2006-2013
- Project Summary
Final Progress Reports
Inflammatory episodes are common in people and animals and are precipitated by numerous stimuli. Many of these episodes do not result in overt tissue injury or disease; in fact, they are beneficial in that they rid the body of unwanted pathogens. Nonetheless, it has long been appreciated that inflammatory mediators participate in a variety of adverse health conditions such as rheumatoid arthritis, cardiovascular disease and asthma. The factors that cause normally harmless episodes of inflammation to culminate in disease are largely unknown but likely include genetic and environmental influences. Exposure to environmental chemicals such as aryl hydrocarbon receptor (AhR) ligands could contribute to individual susceptibility to disease by enhancing inflammatory responses or by providing a stimulus that precipitates injury in the presence of inflammation. The goal of the proposed research is to test the hypothesis that AhR ligands enhance inflammatory responses that can lead to tissue injury, and the tissue of interest is liver.
Dr. Ganey and her research team have continued to investigate the interaction between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and concanavalin A (ConA) that leads to severe liver injury in mice. ConA is a lectin and is used as a model of T cell-mediated diseases, such as some forms of hepatitis. Mice were exposed to TCDD followed 4 days later by administration of ConA. The inflammatory response was greater in the TCDD-treated mice cotreated with ConA than any other group, and liver injury was most severe in this group. Last year the research team discovered that interferon-gamma was critical to the injury and that Fas ligand was selectively upregulated on lymphocytes isolated from the livers of mice treated with TCDD and ConA. In the current year the researchers have explored the roles of hepatic lymphocyte populations in liver injury from cotreatment with TCDD and ConA. Using pharmacologic methods and transgenic mice the research team found that NK cells are the primary contributor to the increase in interferon-gamma production that is critical to liver damage. NKT cells and T cells were required for injury from ConA or from cotreatment with TCDD and ConA; however NK cells appear to play a unique role in the TCDD-induced exaberation of injury from ConA.
The significance of these studies is that the data suggest that a prevalent environmental toxicant, TCDD, can 1) increase the inflammatory response to exogenous stimuli, 2) increase the sensitivity to inflammation-induced tissue damage, and 3) worsen the severity of injury from inflammation, such as occurs during viral hepatitis.