The Ah Receptor Is Not Involved in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated Apoptosis in Human Leukemic T Cell Lines

Hossain, Anwar; Tsuchiya, Shigeru; Minegishi, Masayoshi; Osada, Motonobu; Ikawa, Shuntaro; Tezuka, Fumi Aki; Kaji, Mitsuji; Konno, Tasuke; Watanabe, Minro; Kikuchi, Hideaki

doi:10.1074/jbc.273.31.19853

Cited by 66 publications

(45 citation statements)

References 45 publications

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“…A recent study by Tian et al (36) demonstrated physical interaction of the AHR with NF-B, leading to mutual repression in their system. Upon exposure to TCDD, c-jun, c-fos, and c-Jun N-terminal kinase induction has been observed in hepatoma cell lines (37,30) and in Jurkat cells (38). Thus, indirect up-regulation of IL-2 by TCDD via these factors is possible.…”

Section: Discussionmentioning

confidence: 92%

The MurineIL-2Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family

Jeon¹,

Esser²

2000

The Journal of Immunology

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Signaling through the TCR and costimulatory signals primarily control transcription of the IL-2 gene in naive T cells. The minimal promoter necessary for this expression lies proximal, between −300 and the transcription start site. We had previously shown that activation of the arylhydrocarbon receptor (AHR), a member of the bHLH-PAS family of transcription factors, leads to increased mRNA expression of IL-2 in murine fetal thymocytes. The AHR is abundant in the thymus and may play a role for the development of the immune system. Moreover, its overactivation by chemicals such as dioxins leads to immunosuppression and thymic involution. Binding motifs for the liganded AHR can be identified in the distal region −1300 to −800 of the mouse IL-2 promoter. We show here that these DNA motifs, the so-called dioxin response elements, after binding to the liganded AHR are sufficient to transactivate luciferase expression in a reporter gene system. The IL-2 gene can be induced by the AHR also in thymocytes in vivo after injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent ligand of the AHR. The AHR mediates the IL-2 induction as shown with AHR-deficient mice. However, in spleen cells in vitro costimulation via the TCR is necessary for optimal IL-2 gene induction. Thus, the IL-2 promoter region contains novel distal regulatory elements that can be addressed by the AHR to induce IL-2 and can cooperate with the proximal promoter in this.

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Section: Discussionmentioning

confidence: 92%

The MurineIL-2Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family

Jeon¹,

Esser²

2000

The Journal of Immunology

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“…Although AhR is a receptor for TCDD, AhR-independent effects of TCDD have also been reported (Hossain et al, 1998;Ahmed et al, 2005). Differentiated THP-1 macrophages were treated with α-naphthoflavone (α-NF), an AhR antagonist, together with TCDD.…”

Section: Ahr Mediates Up-regulation Of Tnf-α Expression By Tcddmentioning

confidence: 99%

“…In addition to its activity as a transcription factor, the ligand binding to AhR also triggers signal transduction pathways. However, this receptor-based model cannot explain all the biological effects of TCDD, and AhR-independent effects of TCDD have also been reported (Hossain et al, 1998;Ahmed et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Signaling pathway for 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages

Cheon

Woo²,

Lee³

et al. 2007

Exp Mol Med

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Abstract2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypic halogenated aromatic hydrocarbon (HAH), is known as one of the most potent toxicants. At least a part of its toxic effects appears to be derived from its ability to induce TNF-α production. However, the signaling pathway of TCDD that leads to TNF-α expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-α expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-α in a dose-and time-dependent manner. α-Naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-α at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the increase of TNF-α expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-α expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-α expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with α-NF prevented it. ERK was found to be a downstream effector of EGFR activation in the signaling pathway leading to TNF-α production after TCDD stimulation. Activation of ERK was observed from 30 min after TCDD treatment. PD98059, an inhibitor of the MEK-ERK pathway, completely prevented the TNF-α mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an EGFR inhibitor, as well as α-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-α production by TCDD in differentiated THP-1 macrophages is AhR-dependent and involves activation of EGFR and ERK, but not c-Src, JNK, nor p38 MAPK. A signaling pathway is proposed where TCDD induces sequential activation of AhR, EGFR and ERK, leading to the increased expression of TNF-α.

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“…Immunosuppression, tumor promotion, and teratogenesis are well known toxic effects of these compounds in vertebrates (1)(2)(3)(4).…”

mentioning

confidence: 99%

Suppression by p38 MAP Kinase Inhibitors (Pyridinyl Imidazole Compounds) of Ah Receptor Target Gene Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the Possible Mechanism

Shibazaki

Takeuchi

Ahmed

et al. 2004

Journal of Biological Chemistry

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Cytochrome P-450 1A1 (CYP1A1) is known to be induced by aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), through activation of the aryl hydrocarbon receptor (AhR). We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 M each; pyridinyl imidazole compounds) suppressed CYP1A1-mRNA induction by TCDD (2 nM) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and also suppressed CYP1B1-mRNA induction by TCDD (2 nM) in human breast adenocarcinoma MCF7 cells. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, also suppressed CYP1A1-mRNA induction by TCDD. Moreover, overexpression of a dominantnegative gene for p38 MAP kinase in Hepa-1 cells did not suppress Cyp1a1 reporter gene induction by TCDD. Therefore, the suppression of Cyp1a1 transcription by pyridinyl imidazole compounds is not because of their inhibition of p38 MAP kinase activity. Because SB203580 did not inhibit in vitro AhR transformation by TCDD, this compound was not acting as a simple AhR antagonist. SB203580 decreased TCDD-induced histone acetylation levels in the region of the Cyp1a1 gene promoter, especially around the TATA box sequence. This result suggests the possibility that pyridinyl imidazole compounds suppress the recruitment of some co-activator that has the histone acetyltransferase activity necessary for CYP1A1-mRNA transcription.

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The Ah Receptor Is Not Involved in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated Apoptosis in Human Leukemic T Cell Lines

Cited by 66 publications

References 45 publications

The MurineIL-2Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family

The MurineIL-2Promoter Contains Distal Regulatory Elements Responsive to the Ah Receptor, a Member of the Evolutionarily Conserved bHLH-PAS Transcription Factor Family

Signaling pathway for 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages

Suppression by p38 MAP Kinase Inhibitors (Pyridinyl Imidazole Compounds) of Ah Receptor Target Gene Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the Possible Mechanism

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