This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The immune system is exquisitely sensitive to toxicity resulting from exposure to halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD and related compounds exert their toxic effects by binding to the aryl hydrocarbon receptor (AhR), a soluble, ligand-activated transcription factor. Exposure of rodents to TCDD alters the activation, proliferation and trafficking of lymphocytes and modulates lymphocyte functions, including cytokine production and cytolytic activity. Numerous studies indicate that such AhR-mediated changes in the immune system culminate in decreased host resistance to a variety of pathogens, yet less is known about the ramifications of AhR activation on the immune-regulated homeostasis of organs outside of the immune system. Accumulating evidence indicates that the innate immune system, traditionally considered a non-specific, first line of defense during pathogen exposure, plays a fundamental role in developmental processes and stress responses. In the liver, activation of the innate immune system coincides with cirrhosis, fulminant hepatitis, ischemia-reperfusion injury, as well as regeneration. We have previously demonstrated that exposure to TCDD suppresses liver regeneration following PH. Herein we propose that AhR-mediated alterations in immune function contribute to this suppression. These studies will test the hypothesis that AhR activation by TCDD exacerbates the activation of NKT and NK cells in the liver, resulting in diminution of the regenerative response. This hypothesis will be tested in the context of the following three aims: 1) characterize the consequences of AhR activation on the proliferation, recruitment and activation of intrahepatic lymphocytes (NK and NKT cells) in the regenerating liver;2) investigate how AhR activation alters the cytokine milieu during liver regeneration;and 3) determine if NK and NKT cells are required for the AhR-mediated suppression of liver regeneration. Results from these studies will shed light on how exposure to immunomodulatory environmental toxicants, such as dioxin, affect normal physiological processes in the liver, about which very little is known. Furthermore, these studies will expand our understanding of how liver regeneration is regulated by the immune system. This information may be useful in developing therapeutic strategies to promote or inhibit hepatocyte proliferation during treatment of liver disease. The immune system lends itself easily to our central theme of """"""""Cell Signaling,"""""""" both through cell-cell interactions, and through intracellular activation and suppression mechanisms.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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University of Idaho
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