Dexamethasone increases αvβ3 integrin expression and affinity through a calcineurin/NFAT pathway

The purpose of this study was to determine how dexamethasone (DEX) regulates the expression and activity of alpha v beta 3 integrin. FACS analysis showed that DEX treatment induced expression of an activated alpha v beta 3 integrin. Its expression remained high as long as DEX was present and continued following DEX removal. FACS analysis showed that the upregulation of alpha v beta 3 integrin was the result of an increase in the expression of the beta 3 integrin subunit. By real time qPCR, DEX treatment induced a 62-fold increase (p <0.04) in in integrin mRNA by day 2 compared to control and remained elevated for 6 days of treatment and then an additional 10 days once the DEX was removed. The increase in beta 3 integrin triRNA levels required only 1 day of DEX treatment to increase levels for 4 days in the absence of DEX. In contrast, DEX did not alter beta 3 integrin mRNA or protein levels. The DEX-induced upregulation of beta 3 integrin mRNA was partly due to an increase in its half-life to 60.7 h from 22.5 h in control cultures (p <0.05) and could be inhibited by R1J486 and cycloheximide, suggesting that DEXinduced de novo protein synthesis of an activation factor was needed. The calcineurin inhibitors cyclosporin A (CsA) and FK506 inhibited the DEX induced increase in beta 3 integrin mRNA. In summary, the DEX-induced increase in beta 3 integrin is a secondary glucocorticoid response that results in prolonged expression of alpha v beta 3 integrin and the upregulation of the beta 3 integrin subunit through the calcineurin/NFAT pathway. (C) 2013 Elsevier B.V. All rights reserved.