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 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.
Footnotes
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This study was supported by departmental funding and by grants from the Else Kroener-Fresenius-Stiftung (1087002001), Bad Homburg, Germany.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.038141.
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ABBREVIATIONS: IL, interleukin; AP-1, activator protein 1; CaMKII, calmodulin kinase II; CD, cluster of differentiation; JNK, c-Jun NH2-terminal kinase; LAT, linker for activation of T-cells; MAP, mitogen activated protein; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T-cells; PKC, protein kinase C; ERK, extracellular signal-regulated kinase; FACS, fluorescence-activated cell sorting; LDH, lactate dehydrogenase; PMA, phorbol 12-myristate 13-acetate; ELISA, enzyme-linked immunosorbent assay; RBD, Ras binding domain; GTPγS, guanosine 5′-O-(3-thiotriphosphate).
- Received May 15, 2007.
- Accepted September 18, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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