Mutant Glucocorticoid Receptor Binding Elements on the Interleukin-6 Promoter Regulate Dexamethasone Effects

Abstract

BackgroundGlucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines. ResultsFive putative GR binding sites and other transcriptional factor binding sites were identified on the interleukin (IL)-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, NF-κB, AP-1, and Sp1-2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The first and third GR binding sites (GR2 and GR3) were noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation. ConclusionsWe concluded that selective GR2 and GR3 modulators might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process.