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Research ArticleArticle

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

Narendra P. Singh, Mitzi Nagarkatti and Prakash Nagarkatti
Molecular Pharmacology June 2008, 73 (6) 1722-1735; DOI: https://doi.org/10.1124/mol.107.043406
Narendra P. Singh
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Mitzi Nagarkatti
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Prakash Nagarkatti
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Abstract

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 TCDD-induced 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.

Footnotes

  • This work was funded in part by National Institutes of Health Grants P01-AT03961, R01-ES09098, R01-DA016545, R01-AI058300, R01-AI053703, R01-HL058641, and R21-DA014885; A. D. Williams Trust Funds (to N.P.S.); and an American Cancer Society Institutional grant (to N.P.S.).

  • ABBREVIATIONS: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; DRE, dioxin responsive elements; c-FLIP, cellular FLICE inhibitory protein; DC, dendritic cell; AhR KO, aryl hydrocarbon receptor knockout; Ova, ovalbumin; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PE, phycoerythrin; FasL, Fas ligand; HRP, horseradish peroxidase; Ab, antibody; PCR, polymerase chain reaction; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; ANOVA, analysis of variance; ANF, α-naphthoflavone; ConA, concanavalin A; FITC, fluorescein isothiocyanate; LPS, lipopolysaccharide; RT-PCR, reverse transcriptase-polymerase chain reaction; bp, base pair(s); ΔΨm, mitochondrial membrane potential; DiOC6,3′-dihexyloxacarboeczyme; siRNA, small interfering RNA; APC, antigen-presenting cell; mAb, monoclonal antibody; Z-, N-benzyloxycarbonyl-; FMK, fluoromethyl ketone.

    • Received November 10, 2007.
    • Accepted March 7, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

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

Narendra P. Singh, Mitzi Nagarkatti and Prakash Nagarkatti
Molecular Pharmacology June 1, 2008, 73 (6) 1722-1735; DOI: https://doi.org/10.1124/mol.107.043406

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Research ArticleArticle

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

Narendra P. Singh, Mitzi Nagarkatti and Prakash Nagarkatti
Molecular Pharmacology June 1, 2008, 73 (6) 1722-1735; DOI: https://doi.org/10.1124/mol.107.043406
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