Tumor Necrosis Factor-α Inhibits Aquaporin 5 Expression in Mouse Lung Epithelial Cells

Abstract

Aquaporin 5 (AQP5), the major water channel expressed in alveolar, tracheal, and upper bronchial epithelium, is significantly down-regulated during pulmonary inflammation and edema. The mechanisms that underlie this decrease in AQP5 levels are therefore of considerable interest. Here we show that AQP5 expression in cultured lung epithelial cells is decreased 2-fold at the mRNA level and 10-fold at the protein level by the proinflammatory cytokine tumor necrosis factor α (TNF-α). Treatment of murine lung epithelial cells (MLE-12) with TNF-α results in a concentration- and time-dependent decrease in AQP5 mRNA and protein expression. Activation of the p55 TNF-α receptor (TNFR1) with an agonist antibody is sufficient to cause decreased AQP5 expression, demonstrating that the TNF-α effect is mediated through TNFR1. Inhibition of nuclear factor κB (NF-κB) translocation to the nucleus blocks the effect of TNF-α on AQP5 expression, indicating that activation of NF-κB is required, whereas inhibition of extracellular signal-regulated or p38 mitogen-activated protein kinases showed no effect. These data show that TNF-α decreases AQP5 mRNA and protein expression and that the molecular pathway for this effect involves TNFR1 and activated NF-κB. The ability of inflammatory cytokines to decrease aquaporin expression may help explain the connection between inflammation and edema.