Involvement of Na(+), K (+)-ATPase and its inhibitors in HuR-mediated cytokine mRNA stabilization in lung epithelial cells

Cell Mol Life Sci. 2011 Jan;68(1):109-24. doi: 10.1007/s00018-010-0444-1. Epub 2010 Jul 8.

Abstract

Increasing evidence demonstrates that Na(+), K(+)-ATPase plays an important role in pulmonary inflammation, but the mechanism remains largely unknown. In this study, we used cardiotonic steroids as Na(+), K(+)-ATPase inhibitors to explore the possible involvement of Na(+), K(+)-ATPase in pulmonary epithelial inflammation. The results demonstrated that mice after ouabain inhalation developed cyclooxygenase-2-dependent acute lung inflammation. The in vitro experiments further confirmed that Na(+), K(+)-ATPase inhibitors significantly stimulated cyclooxygenase-2 expression in lung epithelial cells of human or murine origin, the process of which was participated by multiple cis-elements and trans-acting factors. Most importantly, we first described here that Na(+), K(+)-ATPase inhibitors could evoke a significant Hu antigen R nuclear export in lung epithelial cells, which stabilized cyclooxygenase-2 mRNA by binding with a proximal AU-rich element within its 3'-untranslated region. In conclusion, HuR-mediated mRNA stabilization opens new avenues in understanding the importance of Na(+), K(+)-ATPase, as well as its inhibitors in inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antigens, Surface / metabolism
  • Antigens, Surface / physiology*
  • Calcium Signaling
  • Cardiac Glycosides / pharmacology
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Humans
  • Immunoprecipitation
  • Lung / metabolism
  • Mice
  • Ouabain / pharmacology
  • Pneumonia / chemically induced
  • Pneumonia / enzymology
  • Pneumonia / genetics*
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleoproteins / metabolism
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Sodium-Potassium-Exchanging ATPase / physiology*

Substances

  • Antigens, Surface
  • Cardiac Glycosides
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Enzyme Inhibitors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ribonucleoproteins
  • messenger ribonucleoprotein
  • Ouabain
  • Cyclooxygenase 2
  • Extracellular Signal-Regulated MAP Kinases
  • Sodium-Potassium-Exchanging ATPase