Thionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha

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)alpha and interferon (IFN)gamma. In addition, DNA binding of nuclear factor (NF)-kappaB, a proinflammatory transcription factor that regulates both TNFalpha and IFNgamma synthesis, and NF-kappaB-dependent reporter gene expression were reduced. Abrogation of NF-kappaB activity was accompanied by reduced phosphorylation and proteolytic degradation of inhibitor of kappaB (IkappaB)alpha, the inhibitory subunit of the NF-kappaB complex. Carbimazole inhibited NF-kappaB via the small GTPase Rac-1, whereas propylthiouracil inhibited the phosphorylation of IkappaBalpha by its kinase inhibitor of kappaB kinase alpha. Methimazole had no effect on NF-kappaB 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-kappaB 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.