Autotaxin mRNA and protein expression and regulation by salmeterol xinafoate and fluticasone propionate in lung cells (660.13)

Autotaxin (ATX) is the lyso‐phospholipase D enzyme that catalyzes the final step in the synthesis of the lipid mediator lysophosphatidic acid (LPA). ATX, LPA, and LPA receptors in the lung are all strongly associated with the pathology of pulmonary fibrosis, and increasing evidence implicates these same mediators as contributors to asthma. Accordingly, we hypothesized that the asthma drugs salmeterol xinafoate (SX), a long‐acting beta‐2 agonist bronchodilator, and fluticasone propionate (FP), an anti‐inflammatory steroid, would reduce the expression of ATX in lung cells. Cells were treated for 72 hr in the absence or presence of the drugs, alone or in combination. ATX protein assessed by Western blotting of culture medium and ATX mRNA assessed by qPCR were not detected in primary human bronchial epithelial cells or the Beas‐2B bronchial epithelial cell line. ATX protein but not mRNA was detected for human A549 alveolar adenocarcinoma cells and mouse LA4 cells, both of which represent alveolar rather than airway epithelium. Both SX and FP decreased ATX protein expression in these alveolar cells. Stronger ATX protein and mRNA signals were observed in mesenchymal cells, both primary human airway smooth muscle (HASM) cells and the HFL‐1 human fetal lung fibroblast cell line. In these cells, the level of mRNA was decreased moderately by SX, to a greater extent by FP, and decreased yet further by SX + FP. However, ATX protein was minimally decreased or not at all, despite the clear decrease in mRNA. These data reveal interesting cell type‐specific differences in ATX mRNA and protein expression, and they show that asthma therapeutic agents can reduce the expression of ATX in at least some of these cells, which may contribute to their overall therapeutic benefit in patients with asthma. Grant Funding Source : Supported by investigator‐initiated grant 115165 from GlaxoSmithKline