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
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This study was supported by departmental funding and by the Else Kroener-Fresenius-Stiftung (Grant 1087002001), Bad Homburg, Germany.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132407.
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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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