Thionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha.
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.
Humar
Matjaz
M
Center for Clinical Research, Breisacher Strasse 66, D-79106 Freiburg, Germany. humar@ana1.ukl.uni-freiburg.de
Dohrmann
Hannah
H
Stein
Philipp
P
Andriopoulos
Nikolaos
N
Goebel
Ulrich
U
Roesslein
Martin
M
Schmidt
Rene
R
Schwer
Christian I
CI
Loop
Torsten
T
Geiger
Klaus K
KK
Pahl
Heike L
HL
Pannen
Benedikt H J
BH
D013956:Antithyroid Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D013956:Antithyroid Agents; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D051550:I-kappa B Kinase; D020830:rac1 GTP-Binding Protein