Modulation of cytokine production by human mononuclear cells following impairment of Na, K-ATPase activity.

Cytokines, including TNF alpha and IL-l beta, are central to the chronic inflammatory process and tissue damage that characterises diseases such as rheumatoid arthritis. The mechanisms responsible for long-term generation of these molecules are poorly understood. We have previously demonstrated impaired activity of Na, K-ATPase, a key enzyme regulating intracellular cation levels, on rheumatoid mononuclear cells. Mimicking this 'defect' on normal mononuclear cells with ouabain has been shown to induce TNF alpha and, in particular, IL-l beta production, whereas IL-6 synthesis was suppressed. A similar pattern of cytokine generation was noted when mononuclear cells were treated with the sodium ionophore, monensin. Induction of cytokine production was related to up-regulation of the appropriate mRNA, although enhanced secretion of processed IL-l beta was also observed. The mechanism underlying these cellular responses appears to involve sodium/calcium exchange across the cell membrane. Impaired Na,K-ATPase activity might promote pro-inflammatory cytokine secretion in patients with rheumatoid arthritis.