Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway

1 Interleukin-12 (IL-12) may playa central role in the development and prog ression of rheumatoid arthritis by driving the immune response towards T he lper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 pr oduction. In this study we investigated the effect of auranofin (AF), an an ti-rheumatic gold compound, on IL-12 production in mouse macrophages and de ndritic cells, and studied whether AF-mediated inhibition of IL-12 producti on could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells . 2 Treatment with AF significantly inhibited IL-12 production in lipopolysac charide (LPS)stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF di d not influence the cell surface expression of the class-II MHC molecule an d the costimulatory molecules CD80 and CD86. 3 Addition of recombinant IL-12 to cultures of AF-pretreated macrophages an d CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4 The in vivo administration of AF resulted in the inhibition of IL-12 prod uction by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (dec reased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells . 5 These findings may explain some known effects of AF including anti-rheuma tic effects and the inhibition of encephalitogenicity, and point to a possi ble therapeutic use of AF in the Th1-mediated immune diseases such as autoi mmune diseases.