Received for publication May 16, 2007.
Revised September 18, 2007.
Accepted for publication September 18, 2007.

Repression of T-cell function by thionamides is mediated by inhibition of the AP-1/NFAT pathway and is associated with a common structure

Abstract

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 IL-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). Similarly, 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.

Key words: Protein ser/thr Phosphatases, Ras, MAP Kinase, AP-1, NFAT