TY - JOUR T1 - Repression of T-Cell Function by Thionamides Is Mediated by Inhibition of the Activator Protein-1/Nuclear Factor of Activated T-Cells Pathway and Is Associated with a Common Structure JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1647 LP - 1656 DO - 10.1124/mol.107.038141 VL - 72 IS - 6 AU - Matjaz Humar AU - Hannah Dohrmann AU - Philipp Stein AU - Nikolaos Andriopoulos AU - Ulrich Goebel AU - Bernd Heimrich AU - Martin Roesslein AU - Rene Schmidt AU - Christian I. Schwer AU - Alexander Hoetzel AU - Torsten Loop AU - Heike L. Pahl AU - Klaus K. Geiger AU - Benedikt H. J. Pannen Y1 - 2007/12/01 UR - http://molpharm.aspetjournals.org/content/72/6/1647.abstract N2 - Treatment of hyperthyroidism by thionamides is associated with immunomodulatory effects, but the mechanism of thionamide-induced immunosuppression is unclear. Here we show that thionamides directly inhibit interleukin-2 cytokine expression, proliferation, and the activation (CD69 expression) of primary human T lymphocytes. Inhibition of immune function was associated with a repression of DNA binding of the cooperatively acting immunoregulatory transcription factors activator protein 1 (AP-1) and nuclear factor of activated T-cells (NFAT). Likewise, thionamides block the GTPase p21Ras, the mitogen-activated protein kinases, and impair the calcineurin/calmodulin-dependent NFAT dephosphorylation and nuclear translocation. The potency of inhibition correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thio-derivates with a common heterocyclic thioureylene-structure mediate a direct suppression of immune functions in T-cells via inhibition of the AP-1/NFAT pathway. Our observations may also explain the clinical and pathological resolution of some secondary, calcineurin, and mitogen-activated protein kinase-associated diseases upon thionamide treatment in hyperthyroid patients. This offers a new therapeutic basis for the development and application of heterocyclic thio-derivates. The American Society for Pharmacology and Experimental Therapeutics ER -