Synergistic inhibition of T cell proliferation by gold sodium thiomalate and auranofin.
OBJECTIVE
Gold compounds have been employed as therapeutic agents for rheumatoid arthritis (RA) for many years, but the molecular mechanism of their action is unknown. Our studies were undertaken to compare the immunosuppressive activities of parenteral gold (gold sodium thiomalate; GSTM) and orally active gold (auranofin; AF).


METHODS
The effects of GSTM and AF on in vitro models of human T cell activation were examined.


RESULTS
GSTM and AF were found to exert a synergistic inhibitory effect on human T lymphocyte proliferation in vitro. The concentrations of GSTM and AF that synergistically inhibit T cell proliferation were easily attainable in the serum or synovium of patients treated with these agents. The synergistic inhibitory effect of GSTM and AF was not apparent when interleukin 2 (IL-2)R expression or IL-2 production was examined. The inhibitory effects of GSTM and AF could not be explained by a synergistic effect on proximal signal pathways.


CONCLUSIONS
Our results demonstrate that GSTM and AF exert distinct effects on T cell responsiveness and together synergistically inhibit mitogen induced T cell proliferation. These results suggest the possibility that the combination of GSTM and AF may exert a heightened therapeutic effect in RA compared to the action of either agent alone.
Hashimoto
K
K
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
Whitehurst
C E
CE
Lipsky
P E
PE
D001310:Auranofin / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D017612:Gold Compounds / Q000494:pharmacology; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1; D008934:Mitogens / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017612:Gold Compounds; D007295:Inositol Phosphates; D007376:Interleukin-2; D008934:Mitogens; D015375:Receptors, Interleukin-2; D006052:Gold Sodium Thiomalate; D001310:Auranofin; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate