Effects of disease-modifying antirheumatic drugs on macrophage signal transduction and the induction of proinflammatory cytokines

Sammanfattning: Rheumatoid arthritis (RA) is probably the most common source of treatable disability in the Western world. There are several disease-modifying antirheumatic drugs (DMARDs), which have proven to be of therapeutic efficacy in RA, but the lack of a potent, reliable treatment for early RA is a major problem in modern medicine. An obvious line of approach in the quest for better antirheumatic drugs is to determine, as closely as possible, the mechanisms of action of the existing DMARDs. In this thesis, several DMARDs have been tested using mouse macrophages. A system of assays has been used to determine their effects on some identified steps in macrophage signal transduction, like the receptor-mediated activation of phospholipase C, the activation of protein kinase C, the up-regulation of the macrophage high-molecular phospholipase A2 and the release of bioactive eicosanoids. The effects of these DMARDs on the induction and release of the key proinflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) has also been determined. The DMARDs auranofin, tenidap and antimalarials all inhibit arachidonate release induced by zymosan. Auranofin and tenidap also have multiple effects on protein phosphorylation. Among the drugs tested, auranofin is the most potent inhibitor of the induction of proinflammatory cytokines, irrespective of stimulus. Tenidap inhibits the zymosan-induced expression of IL-1 and TNF-alpha. It also inhibits the LPS-induced expression of IL-1, but potentiates the expression of TNF-alpha due to its cyclooxygenase inhibition. The antimalarial compounds, particularly quinacrine, also inhibit the induction of IL-1 and TNF-alpha. Hydrophilic gold compounds, D-penicillamine, methotrexate and sulfasalazine do not affect the induction of IL-1 of TNF-alpha in macrophages. Three drugs (auranofin, tenidap and quinacrine) that inhibit zymosan-induced phospholipase A2 activation also inhibit the zymosan-induced expression of IL-1 and TNF-alpha. It is interesting to speculate that there might be a common step in the MAP kinase cascade, leading to phospholipase A2 up-regulation and the activation of NK-kappaB and/or other transcription factors regulating the induction of IL-1 and TNF-alpha. Considering the pivotal importance of TNF-alpha and IL-1 in RA, it is interesting that several DMARDs act as inhibitors of the induction of these cytokines in macrophages.