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.