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.
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.
Humar
Matjaz
M
Center for Clinical Research, Breisacher Strasse 66, D-79106 Freiburg, Germany. humar@ana1.ukl.uni-freiburg.de
Dohrmann
Hannah
H
Stein
Philipp
P
Andriopoulos
Nikolaos
N
Goebel
Ulrich
U
Heimrich
Bernd
B
Roesslein
Martin
M
Schmidt
Rene
R
Schwer
Christian I
CI
Hoetzel
Alexander
A
Loop
Torsten
T
Pahl
Heike L
HL
Geiger
Klaus K
KK
Pannen
Benedikt H J
BH
D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013858:Thiobarbiturates / Q000737:chemistry / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000502:physiology*
D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D013858:Thiobarbiturates; D018808:Transcription Factor AP-1