Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update

Gold was first used 90 years ago by Robert Koch for the treatment of tuberculosis based on the assumption that rheumatoid arthritis was caused by microbacteria. It soon became clear that this would not explain the action of gold in rheumatoid arthritis, and since then scientists have been struggling to elucidate the mechanisms of gold's action in the treatment of rheumatic diseases. In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. In any case, also based on recent studies the reactivity of gold compounds with thiol groups appears to the predominant factor. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. Especially peptide antigens, which contain sulfur such as cysteine and methionine, are important. Moreover, it could be shown that gold suppresses NF-kappa B binding activity as well as the activation of the I-kappa B-kinase. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-alpha, interleukin-1 and interleukin-6. On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Moreover, the activation of T-cells is inhibited. On the effector level, gold inhibits proteolytic enzymes and can result in the destruction of synovial fibroblasts. In conclusion, gold remains one of the most fascinating antirheumatic drugs with multiple modes of actions. The future analysis of molecular mechanisms, especially with regard to signal transduction, will lead to new fundamental knowledge of gold action, possible allowing a further understanding of the pathogenesis of rheumatoid arthritis.