The role of intracellular cations in the expression of pro-inflammatory cytokines in rheumatoid arthritis

  • Andrew David Foey

Student thesis: Doctoral ThesisPhD


Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated, in part, by pro-inflammatory cytokines such as IL-1β, TNFα and IL-6. Many factors may contribute to cytokine imbalances in this disease, for example, biochemical modulation of PBMCs and their membranes. A key membrane protein is the Na/K-ATPase (sodium pump) responsible for ionic homeostasis. Sodium pump activity on rheumatoid PBMCs was 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 [Na+]i levels and rapidly induced IL-1β and TNFα 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 rheumatoid synovial fibroblasts where ouabain induced IL-6; IL-1β and TNFα, 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 [Ca2+]i brought about the induction of IL-1β and TNFα in PBMCs with a corresponding repression of IL-6 production.

The data obtained in this study suggest that impaired Na/K-ATPase activity in rheumatoid cells, through elevations in intracellular cation levels, might help promote over-production of IL-1β and TNFα 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.

Date of Award1995
Original languageEnglish
Awarding Institution
  • University of Bath

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