Glucocorticoids modulate NF-κB-dependent gene expression by up-regulating FKBP51 expression in Newcastle disease virus-infected chickens

Abstract FK506-binding protein 51(FKBP51, coded by FKBP5 ) is a co-chaperone molecule that interacts with the chaperone HSP90 and the glucocorticoid receptor (GR) in an inactive GR complex. It is a negative regulator of glucocorticoid action and is replaced by the positive regulator, FK506-binding protein 52 (FKBP52, coded by FKBP4 ) when hormone binds to GR, which renders the GR complex active. In this study, we found that the expression of FKBP51 mRNA in 12 organs of Newcastle disease virus (NDV)-infected chickens was robustly induced. The level of corticosterone in NDV-infected chickens was also elevated, approximately 2- to 6.5-fold in the organs compared to non-infected control chickens. The induction of FKBP51 mRNA expression was reproduced by dexamethasone treatment, indicating a role for glucocorticoids in the systemic induction of FKBP51 mRNA expression. In chicken UMNSAH/DF-1 cells, nuclear factor kappaB (NF-κB) was activated in an FKBP51-dependent manner. Regulation of the three NF-κB-dependent, anti-apoptotic genes, bcl-2 , bcl-x and bfl-1 / A1 was investigated in UMNSAH/DF-1 cells. Dexamethasone treatment of UMNSAH/DF-1 cells resulted in up-regulation of bcl-2 , and down-regulation of bcl-x and bfl-1 / A1 . Expression of FKBP51 also resulted in down-regulation of bfl-1/A1 , but had no effect on bcl-2 and bcl-x , suggesting the involvement of glucocorticoid-FKBP51-NF-κB signaling in the regulation of expression of bfl-1 / A1 in UMNSAH/DF-1 cells. We observed organ-specific up- or down-regulation of expression of, bcl-2 , bcl-x and bfl-1/A1 in NDV-infected and dexamethasone-treated chickens. Differential regulation of bfl-1/A1 , bcl-2 and bcl-x upon NDV-infection and dexamethasone treatment suggests that additional factors are involved in the regulation of these genes. These results suggest that systemic elevation of FKBP51 in NDV-infected chickens activates NF-κB, which cooperates with other factors to regulate the expression of NF-κB-dependent genes.