Mutant glucocorticoid receptor binding elements on the interleukin-6 promoter regulate dexamethasone effects

Chang, Wen-Teng; Hong, Ming-Yuan; Chen, Chien-Liang; Hwang, Chi-Yuan; Tsai, Cheng-Chieh; Chuang, Chia-Chang

BACKGROUND: Glucocorticoids (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, such as interleukin (IL)-6. RESULTS: Five putative GR binding sites and other transcriptional factor binding sites were identified on theIL-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, nuclear factor-kappa B (NF-κB), activator protein (AP)-1, and specificity protein (Sp)1–2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The second GR binding site (GR2) was noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation. CONCLUSIONS: We concluded that selective GR2 modulator might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12865-021-00413-z.