MODULATION OF CYTOKINE PRODUCTION BY HUMAN MONONUCLEAR-CELLS FOLLOWING IMPAIRMENT OF NA,K-ATPASE ACTIVITY

Cytokines, including TNF alpha and IL-1 beta, are central to the chron ic 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 previous ly demonstrated impaired activity of Na,K-ATPase, a key enzyme regulat ing intracellular cation levels, on rheumatoid mononuclear cells. Mimi cking this 'defect' on normal mononuclear cells with ouabain has been shown to induce TNF alpha and, in particular, IL-1 beta production, wh ereas IL-6 synthesis was suppressed. A similar pattern of cytokine gen eration was noted when mononuclear cells were treated with the sodium ionophore, monensin. Induction of cytokine production was related to u p-regulation of the appropriate mRNA, although enhanced secretion of p rocessed IL-1 beta was also observed. The mechanism underlying these c ellular responses appears to involve sodium/calcium exchange across th e cell membrane. Impaired Na,K-ATPase activity might promote pro-infla mmatory cytokine secretion in patients with rheumatoid arthritis.