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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

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

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.

Received for publication May 15, 2007.

Accepted for publication September 18, 2007.

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

This article has been cited by other articles:

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