Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits the activity of T cell protein kinase C.

Abstract

Previous studies have shown that the gold compounds, gold sodium thiomalate (GST) and auranofin (AUR), which are effective in the treatment of rheumatoid arthritis, inhibit functional activities ofa variety ofcells, but the biochemical basis of their effect is unknown. In the current studies, human T cell proliferation and interleukin 2 production by Jurkat cells were inhibited by GST or AUR at pharmacologically relevant concentrations. Because it has been documented that protein kinase C (PKC) is involved in T cell activation, the capacity of gold compounds to inhibit PKC partially purified from Jurkat cells was assayed in vitro. GST was found to inhibit PKC in a dose-dependent manner, but AUR caused no significant inhibition of PKC at pharmacologically relevant concentrations. The inhibitory effect of GST on PKC was abolished by 2-mercaptoethanol. To investigate the effect of GST on the regulation of PKC in vivo, the levels of PKC activity in Jurkat cells were examined. Cytosolic PKC activity decreased slowly in a concentration-and time-dependent manner as a result of incubation of Jurkat cells with GST. To ascertain whether GST inhibited PKC translocation and down-regulation, PKC activities associated with the membrane and cytosolic fractions were evaluated after phorbol myristate acetate (PMA) stimulation of GST incubated Jurkat cells. Translocation of PKC was markedly inhibited by pretreatment ofJurkat cells with GST for 3 d, but the capacity of PMA to down-regulate PKC activity in Jurkat cells was not altered by GST preincubation. The functional impact of GST-mediated downregulation of PKC in Jurkat cells was examined by analyzing PMA-stimulated phosphorylation of CD3. Although GST preincubated Jurkat cells exhibited an increased density of CD3, PMA-stimulated phosphorylation of the y chain ofCD3 was markedly inhibited. Specificity for the inhibitory effect of GST on PKC was suggested by the finding that GST did not alter the mitogen-induced increases in inositol trisphosphate levels in Jurkat cells. Finally, the mechanism of the GST-induced inhibition of PKC was examined in detail, using purified PKC subspecies from rat brain. GST inhibited type II PKC more effectively than type III PKC, and also inhibited the enzymatic activity of the isolated catalytic fragment of PKC. The inhibitory effect ofGST on PKC activity

Suppression of interleukin‐2 and interleukin‐2 receptor biosynthesis by gold compounds in in vitro activated human peripheral blood mononuclear cells

“…However, the effect of gold compounds is not limited to monocytes. Direct inhibition by GST and AUR, of purified CD4+ T cell proliferation induced by phorbol myristate acetate and anti-CD3 antibody, was recently reported (12).…”

Genetic association between the PRKCH gene encoding protein kinase Cη isozyme and rheumatoid arthritis in the Japanese population

“…In addition, PKC␤ has been suggested to be a key element in proper T cell migration (46), while PKC has been described as maintaining the integrity of the actin cytoskeleton and mediating interleukin-induced T cell proliferation (47). It is also noteworthy that gold sodium thiomalate, which has been used as a therapeutic agent for RA for many years, is now recognized as a PKC inhibitor, suppressing mitogen-induced T cell proliferation (48).…”

Chrysotherapy: a synoptic review

“…Analysis of the 'Au +3 -specific' T cells show that they reacted to RNaseA peptides, but that recognition of these cryptic peptides did not require the presence of gold [62]. The CD4 + cells are important in the pathogenesis of RA because sodium gold thiomalate can inhibit mitogeninduced DNA synthesis of CD4 + T cells in a dose-dependent manner [42].…”

“…Because the cause or causes of RA are unknown, therapy has largely been directed at suppressing the inflammatory process, with the aim of diminishing symptoms and preventing joint damage [42]. There is no known cure for RA; how- 488 R. Eisler Inflamm.…”