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The Journal of Immunology, 2005, 175: 90-103.
Copyright © 2005 by The American Association of Immunologists

Treatment of Mice with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Leads to Aryl Hydrocarbon Receptor-Dependent Nuclear Translocation of NF-{kappa}B and Expression of Fas Ligand in Thymic Stromal Cells and Consequent Apoptosis in T Cells1

Iris A. Camacho*, Narendra Singh{dagger}, Venkatesh L. Hegde*, Mitzi Nagarkatti* and Prakash S. Nagarkatti2,{dagger}

Departments of* Microbiology and Immunology and {dagger} Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, VA 23298

We investigated the role of aryl hydrocarbon receptor (AhR) in the regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced apoptosis in thymic T cells. AhR knockout (KO) mice were resistant to TCDD-induced thymic atrophy and apoptosis when compared with the AhR wild-type mice. TCDD triggered the expression of several apoptotic genes, including FasL in AhR wild-type but not AhRKO mice. TCDD-induced increase in FasL was seen only in thymic stromal but not thymic T cells. When TCDD-exposed stromal cells were mixed with untreated thymic T cells, increased apoptosis was detected in T cells that involved Fas-FasL interactions. Thus, apoptosis in T cells was not detected when TCDD-treated stromal cells from FasL-defective or AhRKO mice were mixed with wild-type T cells or when TCDD-exposed wild-type stromal cells were mixed with Fas-deficient T cells. TCDD treatment, in vivo and in vitro, led to colocalization and translocation of NF-{kappa}B subunits (p50, p65) to the nucleus in stromal but not T cells from AhR wild-type mice. NF-{kappa}B activation was not observed in stromal cells isolated from TCDD-treated AhRKO mice. Mutations in NF-{kappa}B-binding sites on the FasL promoter showed that TCDD regulates FasL promoter activity through NF-{kappa}B. TCDD treatment in vivo caused activation of the death receptor and mitochondrial pathways of apoptosis. Cross-talk between the two pathways was not necessary for apoptosis inasmuch as TCDD-treated Bid KO mice showed thymic atrophy and increased apoptosis, similar to the wild-type mice. These findings demonstrate that AhR regulates FasL and NF-{kappa}B in stromal cells, which in turn plays a critical role in initiating apoptosis in thymic T cells.




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