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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Center for Clinical Research, Department of Anesthesiology, University Hospital Freiburg, Freiburg, Germany (M.H., H.D., P.S., U.G., M.R., R.S., C.I.S., T.L., K.K.G., H.L.P.); Department of Medicine IV and Kidney Research Center Cologne, University of Cologne, Cologne, Germany (N.A.); and Department of Anesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany (B.H.J.P.)

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

Address correspondence to: Dr. Matjaz Humar, Center for Clinical Research, Breisacher Strasse 66, D-79106 Freiburg, Germany. E-mail: humar{at}ana1.ukl.uni-freiburg.de

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