TCDD-induced apoptosis in EL-4 cells deficient of the aryl hydrocarbon receptor and down-regulation of IGFBP-6 prevented the apoptotic cell death

Park, Joo-Hung; Hahn, E. Adelaide; Kong, Ji-Hye; Cho, Hyun Jin; Yoon, Chun-Sik; Cheong, Seon-Woo; Oh, Gap-Soo; Youn, Hyun-Joo

doi:10.1016/s0378-4274(03)00259-5

Cited by 24 publications

(8 citation statements)

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“…For example, in vitro studies using T cell lines such as Jurkat, have shown that TCDD activates MAPK-signaling pathways including JNK and ERK, suggesting that MAPK pathways may be involved in TCDDinduced cell death (35). In EL-4 T cells, it was shown that insulinlike growth factor-binding protein-6 was found to mediate the immunotoxic effects of TCDD in an AhR-independent pathway (13).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to Fas and FasL, TCDD induces the transcriptional expression of several proapoptotic genes in the thymus and spleen (12). In vitro studies using human leukemic T cell lines and EL-4 mouse thymoma cell lines demonstrated enhanced apoptosis following TCDD treatment via AhR-independent but caspase-dependent mechanisms (13,14). Interestingly, TCDDexposed leukemic T cell lines exhibited down-regulation of bcl-2 and induction of the JNK pathway (14), implicating a possible role for the mitochondrial pathway.…”

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confidence: 99%

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

Camacho

Singh

Hegde

et al. 2005

The Journal of Immunology

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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-κB subunits (p50, p65) to the nucleus in stromal but not T cells from AhR wild-type mice. NF-κB activation was not observed in stromal cells isolated from TCDD-treated AhRKO mice. Mutations in NF-κB-binding sites on the FasL promoter showed that TCDD regulates FasL promoter activity through NF-κB. 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-κB in stromal cells, which in turn plays a critical role in initiating apoptosis in thymic T cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Camacho

Singh

Hegde

et al. 2005

The Journal of Immunology

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“…Overexpression of IGFBP-6 arbitrarily in non-small cell lung cancer cells activates programmed cell death (52). With TCDD-induced expression of IGFBP-6, a high degree of IGFBP-6 elevation appeared to enhance apoptosis, whereas a reduction of IGFBP-6 inhibited TCDD from inducing apoptosis in thymoma cells (53). Inactivating the expression of IGFBP-6 in colon cancer cells resulted in a gain of cell proliferation, suggesting that IGFBP-6 may be inhibitory for cell growth (43).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Identification of Insulin-like Growth Factor-binding Protein-6 Induced by Sublethal H2O2 Stress from Human Diploid Fibroblasts

Xie

Tsaprailis²,

Chen

2005

Molecular & Cellular Proteomics

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Fibroblasts are the most ubiquitous cell types within our body. They produce various factors to maintain the texture and structure of a particular organ or tissue. To identify protein factors secreted by fibroblasts and alteration of these protein factors upon oxidative stress, HCA 3 human skin diploid fibroblasts were exposed to a sublethal dose of H 2 O 2 , which induces a prematurely senescent phenotype. Conditioned media from prematurely senescent cells versus control cells were analyzed for proteins using an LC-MS/MS-based proteomic technique. Collagen ␣1(VI), collagen ␣2(I), fibronectin, lumican, and matrix metalloproteinase 2 were among the proteins consistently detected from control and H

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“…The data obtained from the present study corroborates the critical role played by AhR in peripheral activated T-cell apoptosis by demonstrating 1) up-regulated expression of AhR, Fas, and FasL upon T-cell activation; 2) minimal apoptosis in activated T cells from AhR KO mice; and 3) complete block of TCDD-mediated apoptosis of T cells in the presence of ANF, an AhR antagonist. It should be noted that Park et al (2003) have shown that TCDD triggered apoptosis in AhR-deficient EL4 cells through insulin-like growth-binding protein-6. In primary activated T cells from AhR KO mice, we also noticed that at higher concentrations of TCDD (1000 nM), there was a low level of apoptosis, thereby suggesting that TCDD at very high concentrations may mediate apoptosis through AhRindependent mechanisms.…”

Section: Role Of Dendritic Cells In Tcdd-induced T-cell Apoptosismentioning

confidence: 99%

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

Singh

Nagarkatti²,

Nagarkatti

2008

Mol Pharmacol

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Although the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cells in vivo have been well characterized, attempts to reproduce these findings in vitro have not been successful. In the current study, we examined whether activation or the presence of dendritic cells (DCs) would make primary naive T cells from C57BL/6 mice susceptible to TCDD-induced apoptosis in vitro. Although nonactivated primary T cells cultured with 10 to 1000 nM TCDD were relatively resistant to apoptosis, they became sensitive to apoptosis upon activation with concanavalin A (ConA). Moreover, ConA-activated T cells cultured in the presence of DCs showed highest levels of TCDD-induced apoptosis. Likewise, primary T cells from OT.II.2a mice cultured with specific ovalbumin peptide and syngeneic DCs showed higher levels of apoptosis compared with similar nonactivated T cells. T-cell activation led to up-regulation of aryl hydrocarbon receptor (AhR), Fas, and Fas-ligand (FasL) expression. In addition, DC maturation and culture with TCDD caused significant induction of FasL. TCDD-mediated apoptosis in activated peripheral T cells was AhR-dependent. Analysis of why nonactivated T cells are more resistant, whereas activated T cells are sensitive to TCDD-induced apoptosis revealed that TCDD treatment of activated but not nonactivated T cells led to down-regulation of cellular FLICE inhibitory protein (c-FLIP), an inhibitor of apoptosis. Moreover, down-regulation of c-FLIP using small interfering RNA in nonactivated T cells made them sensitive to TCDDinduced apoptosis. The current study demonstrates for the first time that TCDD can induce apoptosis in vitro in peripheral T cells upon activation and in the presence of DCs and that this may be mediated by down-regulation of c-FLIP.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that mediates toxicity through activation of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor and member of the basic helix-loop-helix-Per/Arnt/Sim (periodicity/aryl hydrocarbon receptor nuclear translocator/simple-minded) gene family (Marlowe and Puga, 2005;Bock and Kohle, 2006;Harper et al., 2006). TCDD binds and activates cytosolic AhR attached to 90-kDa heat shock protein; and upon activation, AhR dissociates from 90-kDa heat shock protein, migrates to the nucleus, dimerizes with AhR nuclear translocator (ARNT), and forms AhR/ARNT heterodimer. This in turn binds to dioxin-response elements (DRE), present as cis-acting elements in the regulatory regions of dioxin-responsive genes, and it up-regulates a large set of genes that directly or indirectly participate in TCDD-induced toxicity (Schmidt and

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TCDD-induced apoptosis in EL-4 cells deficient of the aryl hydrocarbon receptor and down-regulation of IGFBP-6 prevented the apoptotic cell death

Cited by 24 publications

References 50 publications

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

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

Proteomic Identification of Insulin-like Growth Factor-binding Protein-6 Induced by Sublethal H2O2 Stress from Human Diploid Fibroblasts

Primary Peripheral T Cells Become Susceptible to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Mediated Apoptosis in Vitro upon Activation and in the Presence of Dendritic Cells

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