Modulation of Na+/K+ exchange potentiates lipopolysaccharide‐induced gene expression in murine peritoneal macrophages

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Abstract
The role of Na+/K+ exchange in regulating lipopolysaccharide (LPS)‐mediated induction of cytokine gene expression has been examined in murine peritoneal macrophages. Depletion of K+ from the culture medium resulted in a three‐ to five‐fold potentiation of tumor necrosis factor‐α (TNFα), KC (gro), and IP‐10 mRNA expression in LPS‐treated macrophages. The potentiating effect was apparently the result of inhibition of Na+/K+ exchange through the Na+/K+‐adenosine triphosphatase (ATPase) because ouabain‐mediated inhibition of Na+/K+‐ATPase was also able to potentiate cytokine mRNA expression as much or more than did K+ depletion. The effects of K+ depletion or ouabain treatment were not caused by depolarization of the macrophage membrane because depolarization mediated by elevating extracellular K+ levels was inhibitory to cytokine mRNA expression. Depletion of Na+ by substitution with cho ine in the culture medium also markedly potentiated LPS‐induced gene expression. The Na+/H+ antiporter was not, however, involved in potentiating cytokine expression because treatment of macrophages with amiloride either had no effect on or was inhibitory to the LPS‐induced changes in mRNA levels. The potentiation of gene expression was selective and was at least partially the result of increased transcriptional activity of each gene. Whereas Na+ depletion and ouabain both inhibited 86Rb+ uptake by macrophages, treatment with LPS had no effect either on Rb+ uptake or on efflux. Thus altered Na+/K+ exchange is not a component of the primary signalling pathway(s) mediating response to LPS. Nevertheless, modulation of macrophage Na+/K+ exchange by agents encountered during an inflammatory response may be an important determinant of the magnitude and quality of specific gene expression.