RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1647
OP 1656
DO 10.1124/mol.107.038141
VO 72
IS 6
A1 Matjaz Humar
A1 Hannah Dohrmann
A1 Philipp Stein
A1 Nikolaos Andriopoulos
A1 Ulrich Goebel
A1 Bernd Heimrich
A1 Martin Roesslein
A1 Rene Schmidt
A1 Christian I. Schwer
A1 Alexander Hoetzel
A1 Torsten Loop
A1 Heike L. Pahl
A1 Klaus K. Geiger
A1 Benedikt H. J. Pannen
YR 2007
UL http://molpharm.aspetjournals.org/content/72/6/1647.abstract
AB 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