Alexandros G .Sfakianakis,ENT,Anapafeos 5 Agios Nikolaos Crete 72100 Greece,00302841026182

Πέμπτη 30 Νοεμβρίου 2017

Proteasome-mediated degradation of collagen III by cortisol in amnion fibroblasts

Rupture of fetal membranes (ROM) can initiate parturition at both term and preterm. Collagen III in the compact layer of the amnion contributes to the tensile strength of fetal membranes. However, the upstream signals triggering collagen III degradation remain mostly elusive. In this study we investigated the role of cortisol regenerated by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in collagen III degradation in human amnion fibroblasts with an aim to seek novel targets for the prevention of preterm premature ROM (PPROM)-elicited preterm birth. Human amnion tissue and cultured amnion tissue explants and amnion fibroblasts were used to study the regulation of collagen III, which is composed of three identical collagen 3A1 chains (COL3A1), by cortisol. Cortisol decreased COL3A1 protein but not mRNA abundance in a concentration-dependent manner. Cortisone also decreased COL3A1 protein, which was blocked by 11β-HSD1 inhibition. The reduction in COL3A1 protein by cortisol was not affected by a transcription inhibitor but further enhanced by a translation inhibitor. Autophagic pathway inhibitor chloroquine or siRNA-mediated knock-down of ATG7, an essential protein for autophagy failed to block cortisol-induced reduction in COL3A1 protein abundance, whereas proteasome pathway inhibitors MG132 and bortezomib significantly attenuated cortisol-induced reduction in COL3A1 protein abundance. Moreover, cortisol increased COL3A1 ubiquitination and the reduction of COL3A1 protein by cortisol was blocked by PYR-41, a ubiquitin-activating enzyme inhibitor. Conclusively, cortisol regenerated in amnion fibroblasts may be associated with rupture of fetal membranes at parturition by reducing collagen III protein abundance through a ubiquitin-proteasome pathway.



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