title: Modulation of Na+/K+ exchange potentiates lipopolysaccharide-induced gene expression in murine peritoneal macrophages.
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-alpha (TNF alpha), 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 choline 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.
authors.affiliation: Research Institute, Cleveland Clinic Foundation, Ohio 44106.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohmori
authors.forename: E
authors.initials: E
authors.lastname: Reynolds
authors.forename: T A
authors.initials: TA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010042:Ouabain / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012414:Rubidium Radioisotopes; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D014409:Tumor Necrosis Factor-alpha; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase