Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids
Sustained incubation with IL-1β promotes a split responsiveness of GC-induced anti-inflammatory genes: selective reduction in FKBP1, IRF8, and TTP, superinduction of IGFBP1 and unchanged DUSP1 and GILZ mRNA expression. Cells were cultured in complete medium (veh/veh, ▲, solid line), pretreated 16 h in vehicle, then treated with 10−8 M DEX alone for the indicated times (veh/DEX, ●, solid line), subjected to sustained IL-1β conditions (16 h 5 ng/mL IL-1β/5 ng/mL IL-1β + 10−8 M DEX for the indicated times, ■, solid grey line), or treated under sustained IL-1β conditions in the presence of IL-1ra (16 h 5 ng/mL IL-1β + IL-1ra/5 ng/mL IL-1β + IL-1ra + 10−8 M DEX for the indicated times, , dashed line). After the indicated treatments, the cells were collected and mRNA extracted and quantitated by real-time RT-PCR. The time-course curves represent the mean ± SEM fold-changes in the expression of FKBP51 (a), GILZ (b), DUSP1 (c), TTP (d), IRF8 (e), and IGFBP1 (f) mRNAs, for each culture condition compared to veh/veh-treated cells at 0 h (). #, veh/DEX-treated versus veh/veh-treated cells. , sustained IL-1β conditions versus DEX alone-treated cells. , differences between cells under sustained IL-1β conditions in the presence or absence of IL-1ra.