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.
Foey
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AD
School of Pharmacy and Pharmacology, University of Bath. Bath Institute for Rheumatic Diseases, UK.
Crawford
A
A
Hall
N D
ND
D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007476:Ionophores / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008985:Monensin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007476:Ionophores; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D010042:Ouabain; D008985:Monensin; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium