Involvement of Na(+), K (+)-ATPase and its inhibitors in HuR-mediated cytokine mRNA stabilization in lung epithelial cells.
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.
Feng
Su
S
The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
Chen
Wei
W
Cao
Dan
D
Bian
Jinjun
J
Gong
Fang-Yuan
FY
Cheng
Wei
W
Cheng
Shun
S
Xu
Qiang
Q
Hua
Zi-Chun
ZC
Yin
Wu
W
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling; D002301:Cardiac Glycosides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D008168:Lung / Q000378:metabolism; D051379:Mice; D010042:Ouabain / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000954:Antigens, Surface; D002301:Cardiac Glycosides; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C026452:messenger ribonucleoprotein; D010042:Ouabain; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D000254:Sodium-Potassium-Exchanging ATPase