Exogenous induction of unphosphorylated PTEN reduces TGFβ-induced extracellular matrix expressions in lung fibroblasts

Transforming growth factor beta (TGF beta) plays an important role in regulating aberrant extracellular matrix (ECM) production from alveolar/epithelial cells (AECs) and fibroblasts in pulmonary fibrosis. Although the tumor suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) can negatively control many TGF beta-activated signaling pathways via the phosphatase activity, hyperactivation of the TGF beta-related signaling pathways is often observed in fibrosis. Loss of PTEN expression might cause TGF beta-induced ECM production. In addition, TGF beta was recently shown to induce loss of PTEN enzymatic activity by phosphorylating the PTEN C-terminus. Therefore, we hypothesized that exogenous transfer of unphosphorylated PTEN (PTEN4A) might lead to reduce TGF beta-induced ECM expression in not only epithelial cells but also fibroblasts. Adenovirus-based exogenous PTEN4A induction successfully reduced TGF beta-induced fibronectin expression and retained beta-catenin at the cell membrane in human epithelial cells. Exogenous unphosphorylated PTEN also attenuated TGF beta-induced ECM production and inhibited TGF beta-induced b-catenin translocation in a human fibroblast cell line and in mouse primary isolated lung fibroblasts. Conversely, TGF beta-induced a-smooth muscle actin expression did not seem to be inhibited in these fibroblasts. Our data suggest that exogenous administration of unphosphorylated PTEN might be a promising strategy to restore TGF beta-induced loss of PTEN activity and reduce aberrant TGF beta-induced ECM production from epithelial cells and fibroblasts in lung fibrosis as compared with wild-type PTEN induction.