Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated, in part, by pro-inflammatory cytokines such a sI L- I P, TNFa andI L-6. Many factors may contribute to cytokine imbalances in this disease, for example, biochemical modulation of PBMCsa ndt heir membranes A. key membrane proteini s the Na/KATPase( sodium pump) responsible for ionic homeostasis Sodiump ump activity on rheumatoid PBMCsw as found to be markedly depressed when compared with healthy control cells possibly through an oxidative mechanism. Inhibition of the sodium pump by a cardiac glycoside inhibitor, ouabain, transiently upregulated[N a'ji levels and rapidly induced IL-10 and TNFa mRNA and protein in human PBMCs. In contrast, IL-6 production was significantly depressed. The sodium ionophore, monensin, caused a similar Na-dependent cytokine response to that of ouabain. This cytokine profile however, was reversed when studying rheumatoids ynovial fibroblasts where ouabain induced I L-6; IL- I and TNFa, on the other hand, were not expressed. An elevation in intracellulars odiumc an causea secondary rise in intracellular calcium levels through the action of a Na/Ca2+ exchanger. In studies using the calcium ionophore, A23187, it was observed that an elevation in [Ca 2+]i brought aboutt he induction of IL- IP and TNF(xi n PBMCs with a corresponding repression of IL-6 production. The data obtained in this study suggest that impaired N a/K-ATPase activity in rheumatoid cells, through elevations in intracellular cation levels, might help promote over-production of IL- IP and TNF(x by monocytes and IL-6 by synovial fibroblasts. This pattern of cytokine production conforms to that observed in rheumatoid synovial tissue in situ, thus supporting a role for this biochemical defect in contributing to the perpetuation of the chronic inflammatory state.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:296313 |
| Date | January 1995 |
| Creators | Foey, Andrew David |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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