The interaction of auranofin and buthionine sulfoximine blocks activation of human peripheral T lymphocytes.
We have previously demonstrated that auranofin, at nanomolar concentrations, enhances T cell activation, as measured by IL-2 release and Tac expression. However, it is not clear how enhanced T cell activation might be related to therapeutic value, since rheumatoid arthritis is widely believed to be associated with overactivation of the immune response. In this study, we show that the action of auranofin on T cell activation is dramatically influenced by the glutathione levels of the responding cells. Under conditions of very low intracellular glutathione where the synthesis of glutathione is blocked, the action of auranofin is converted from enhancement to a profound inhibition of T cell activation. Since glutathione levels in rheumatoid arthritis are known to be abnormally low, these results may explain how auranofin can act to suppress the immunological processes leading to rheumatoid arthritis. In addition, this study further demonstrated the close link which exists between auranofin action and glutathione metabolism in lymphocytes.
Vint
I A
IA
Department of Pharmacology, University College London, United Kingdom.
Chain
B M
BM
Foreman
J C
JC
D001310:Auranofin / Q000494:pharmacology* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000096:biosynthesis*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; D008717:Methionine Sulfoximine; D001310:Auranofin; D019328:Buthionine Sulfoximine; D005978:Glutathione