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