Abstract
The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-β1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-β1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors.
Highlights
The epithelial to mesenchymal transition (EMT) events have been very well defined during embryogenesis, organ development, wound healing and stem cell behaviors [1]
We found that prostaglandin E2 (PGE2) and PGD2 production as well as reduction in transforming growth factor (TGF)-β1-induced ERK1/2 and Akt phosphorylation levels by growth arrest-specific protein 6 (Gas6) were blocked by specific siRNAs for Axl or Mer
In addition to anti-epithelial-mesenchymal transition (EMT) effects, we demonstrated that Gas6/Axl or Mer signaling inhibits TGF-β1-induced migration and invasion of LA-4 and alveolar type II (ATII) epithelial cells (ECs) via PGE2 and PGD2 production
Summary
The epithelial to mesenchymal transition (EMT) events have been very well defined during embryogenesis, organ development, wound healing and stem cell behaviors [1]. This process has been shown to contribute pathologically to organ fibrosis and cancer progression. IPF likely results from recurrent alveolar epithelial cell (EC) injury coupled with accumulation and differentiation of fibroblasts into myofibroblasts, leading to the accumulation of extracellular matrix (ECM) and destruction of the lung parenchyma [5]. Alveolar ECs undergoing epithelial-mesenchymal transition (EMT), a process frequently mediated by TGF-β [6], are a major source of fibroblasts [7,8]. Several drugs are currently used to treat IPF, no proven, efficacious therapies currently exist [9]
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