Glucocorticoids modulate NF-kappaB-dependent gene expression by up-regulating FKBP51 expression in Newcastle disease virus-infected chickens.Mol Cell Endocrinol. 2007 Nov 15; 278(1-2):7-17.MC
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-kappaB) was activated in an FKBP51-dependent manner. Regulation of the three NF-kappaB-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-kappaB 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-kappaB, which cooperates with other factors to regulate the expression of NF-kappaB-dependent genes.