Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

Morzadec, Claudie; Macoch, Mélinda; Robineau, Marc; Sparfel, Lydie; Fardel, Olivier; Vernhet, Laurent

doi:10.1016/J.TAAP.2012.05.004

Title: Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

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Abstract

Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in partmore »« less

Authors:

Morzadec, Claudie; Macoch, Mélinda; Robineau, Marc; Sparfel, Lydie ^[1]; Fardel, Olivier ^[1]; Vernhet, Laurent ^[1]

UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes (France)

Publication Date:: Wed Aug 01 00:00:00 EDT 2012

OSTI Identifier:: 22215857

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 262; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ACETATES; ANTIBODIES; ARSENIC; GENES; HYDROCARBONS; INFLAMMATION; INTERFERON; LEUKEMIA; LYMPHOCYTES; MESSENGER-RNA; MICE; POLYMERASE CHAIN REACTION; RECEPTORS; SECRETION; TRANSCRIPTION FACTORS

Citation Formats


                    Morzadec, Claudie, Macoch, Mélinda, Robineau, Marc, Sparfel, Lydie, Fardel, Olivier, Pôle Biologie, Centre Hospitalier Universitaire, and Vernhet, Laurent. Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes.  United States: N. p., 2012. 
        Web.  doi:10.1016/J.TAAP.2012.05.004.

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                    Morzadec, Claudie, Macoch, Mélinda, Robineau, Marc, Sparfel, Lydie, Fardel, Olivier, Pôle Biologie, Centre Hospitalier Universitaire, & Vernhet, Laurent. Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes.  United States.  https://doi.org/10.1016/J.TAAP.2012.05.004

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                    Morzadec, Claudie, Macoch, Mélinda, Robineau, Marc, Sparfel, Lydie, Fardel, Olivier, Pôle Biologie, Centre Hospitalier Universitaire, and Vernhet, Laurent. 2012.  
        "Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes".  United States.  https://doi.org/10.1016/J.TAAP.2012.05.004.

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@article{osti_22215857,

  title        = {Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes},

  author       = {Morzadec, Claudie and Macoch, Mélinda and Robineau, Marc and Sparfel, Lydie and Fardel, Olivier and Pôle Biologie, Centre Hospitalier Universitaire and Vernhet, Laurent},

  abstractNote = {Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans. -- Highlights: ► Arsenic inhibits secretion of IL-17A from human naïve and memory Th17 lymphocytes. ► Arsenic represses early expression of IL-17A gene in human activated T lymphocytes. ► Arsenic interferes with activation of the JNK/c-Jun pathway in human T lymphocytes.},

  doi          = {10.1016/J.TAAP.2012.05.004},

  url          = {https://www.osti.gov/biblio/22215857},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 262,

  place        = {United States},

  year         = {Wed Aug 01 00:00:00 EDT 2012},

  month        = {Wed Aug 01 00:00:00 EDT 2012}

}

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