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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Thionamides Inhibit the Transcription Factor Nuclear Factor-κB by Suppression of Rac1 and Inhibitor of κB Kinase α

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Torsten Loop, Klaus K. Geiger, Heike L. Pahl and Benedikt H.J. Pannen
Journal of Pharmacology and Experimental Therapeutics March 2008, 324 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.107.132407
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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Martin Roesslein
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Rene Schmidt
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Christian I. Schwer
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Torsten Loop
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Klaus K. Geiger
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Heike L. Pahl
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Benedikt H.J. Pannen
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Abstract

Thionamides, inhibitors of the thyroid peroxidase-mediated iodination, are clinically used in the treatment of hyperthyroidism. However, the use of antithyroid drugs is associated with immunomodulatory effects, and recent studies with thionamide-related heterocyclic thioderivates demonstrated direct anti-inflammatory and immunosuppressive properties. Using primary human T-lymphocytes, we show that the heterocyclic thionamides carbimazole and propylthiouracil inhibit synthesis of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)γ. In addition, DNA binding of nuclear factor (NF)-κB, a proinflammatory transcription factor that regulates both TNFα and IFNγ synthesis, and NF-κB-dependent reporter gene expression were reduced. Abrogation of NF-κB activity was accompanied by reduced phosphorylation and proteolytic degradation of inhibitor of κB (IκB)α, the inhibitory subunit of the NF-κB complex. Carbimazole inhibited NF-κB via the small GTPase Rac-1, whereas propylthiouracil inhibited the phosphorylation of IκBα by its kinase inhibitor of κB kinase α. Methimazole had no effect on NF-κB induction, demonstrating that drug potency correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thioureylenes with a common, heterocyclic structure inhibit inflammation and immune function via the NF-κB pathway. Our results may explain the observed remission of proinflammatory diseases upon antithyroid therapy in hyperthyroid patients. The use of related thioureylenes may provide a new therapeutic basis for the development and application of anti-inflammatory compounds.

Footnotes

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

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

  • doi:10.1124/jpet.107.132407.

  • ABBREVIATIONS: IL, interleukin; NF, nuclear factor; IκB, inhibitor of κB; IKK, inhibitor of κB kinase; CD, cluster(s) of differentiation; ELISA, enzyme-linked immunosorbent assay; TNF, tumor necrosis factor; IFN, interferon; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; PAGE, polyacrylamide gel electrophoresis; GST, glutathione S-transferase; GTPγS, guanosine 5′-3-O-(thio)triphosphate; ZAP, ζ-associated protein; MLK, mixed lineage kinase; MEKK, mitogen-activated protein kinase kinase kinase.

    • Received October 1, 2007.
    • Accepted November 29, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 3
1 Jun 2022
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Thionamides Inhibit the Transcription Factor Nuclear Factor-κB by Suppression of Rac1 and Inhibitor of κB Kinase α

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Torsten Loop, Klaus K. Geiger, Heike L. Pahl and Benedikt H.J. Pannen
Journal of Pharmacology and Experimental Therapeutics March 1, 2008, 324 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.107.132407

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Thionamides Inhibit the Transcription Factor Nuclear Factor-κB by Suppression of Rac1 and Inhibitor of κB Kinase α

Matjaz Humar, Hannah Dohrmann, Philipp Stein, Nikolaos Andriopoulos, Ulrich Goebel, Martin Roesslein, Rene Schmidt, Christian I. Schwer, Torsten Loop, Klaus K. Geiger, Heike L. Pahl and Benedikt H.J. Pannen
Journal of Pharmacology and Experimental Therapeutics March 1, 2008, 324 (3) 1037-1044; DOI: https://doi.org/10.1124/jpet.107.132407
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