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Molecular Pharmacology

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Research ArticleArticle

Repression of T-Cell Function by Thionamides Is Mediated by Inhibition of the Activator Protein-1/Nuclear Factor of Activated T-Cells Pathway and Is Associated with a Common Structure

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Bernd Heimrich, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Alexander Hoetzel, Torsten Loop, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology December 2007, 72 (6) 1647-1656; DOI: https://doi.org/10.1124/mol.107.038141
Matjaz Humar
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Hannah Dohrmann
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Philipp Stein
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Nikolaos Andriopoulos
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Ulrich Goebel
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Bernd Heimrich
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Martin Roesslein
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Rene Schmidt
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Christian I. Schwer
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Alexander Hoetzel
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Torsten Loop
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Heike L. Pahl
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Klaus K. Geiger
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Benedikt H. J. Pannen
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Abstract

Treatment of hyperthyroidism by thionamides is associated with immunomodulatory effects, but the mechanism of thionamide-induced immunosuppression is unclear. Here we show that thionamides directly inhibit interleukin-2 cytokine expression, proliferation, and the activation (CD69 expression) of primary human T lymphocytes. Inhibition of immune function was associated with a repression of DNA binding of the cooperatively acting immunoregulatory transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-cells (NFAT). Likewise, thionamides block the GTPase p21Ras, the mitogen-activated protein kinases, and impair the calcineurin/calmodulin-dependent NFAT dephosphorylation and nuclear translocation. The potency of inhibition correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thio-derivates with a common heterocyclic thioureylene-structure mediate a direct suppression of immune functions in T-cells via inhibition of the AP-1/NFAT pathway. Our observations may also explain the clinical and pathological resolution of some secondary, calcineurin, and mitogen-activated protein kinase-associated diseases upon thionamide treatment in hyperthyroid patients. This offers a new therapeutic basis for the development and application of heterocyclic thio-derivates.

Footnotes

  • This study was supported by departmental funding and by grants from the Else Kroener-Fresenius-Stiftung (1087002001), Bad Homburg, Germany.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.038141.

  • ABBREVIATIONS: IL, interleukin; AP-1, activator protein 1; CaMKII, calmodulin kinase II; CD, cluster of differentiation; JNK, c-Jun NH2-terminal kinase; LAT, linker for activation of T-cells; MAP, mitogen activated protein; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells; PKC, protein kinase C; ERK, extracellular signal-regulated kinase; FACS, fluorescence-activated cell sorting; LDH, lactate dehydrogenase; PMA, phorbol 12-myristate 13-acetate; ELISA, enzyme-linked immunosorbent assay; RBD, Ras binding domain; GTPγS, guanosine 5′-O-(3-thiotriphosphate).

    • Received May 15, 2007.
    • Accepted September 18, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Repression of T-Cell Function by Thionamides Is Mediated by Inhibition of the Activator Protein-1/Nuclear Factor of Activated T-Cells Pathway and Is Associated with a Common Structure

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Bernd Heimrich, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Alexander Hoetzel, Torsten Loop, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology December 1, 2007, 72 (6) 1647-1656; DOI: https://doi.org/10.1124/mol.107.038141

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Research ArticleArticle

Repression of T-Cell Function by Thionamides Is Mediated by Inhibition of the Activator Protein-1/Nuclear Factor of Activated T-Cells Pathway and Is Associated with a Common Structure

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Bernd Heimrich, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Alexander Hoetzel, Torsten Loop, Heike L. Pahl, Klaus K. Geiger and Benedikt H. J. Pannen
Molecular Pharmacology December 1, 2007, 72 (6) 1647-1656; DOI: https://doi.org/10.1124/mol.107.038141
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