Oh Kyu-Seon, Patel Heta, Gottschalk Rachel A, Lee Wai Shing, Baek Songjoon, Fraser Iain D C, Hager Gordon L, Sung Myong-Hee
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity. 2017 Aug 15;47(2):298-309.e5. doi: 10.1016/j.immuni.2017.07.012. Epub 2017 Aug 8.
Despite the widespread use of glucocorticoids (GCs), their anti-inflammatory effects are not understood mechanistically. Numerous investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinical situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we profiled macrophage transcriptional and chromatinscapes with Dexamethasone (Dex) treatment before or after stimulation by lipopolysaccharide (LPS). The late activation of GR had a similar gene-expression profile as from GR pre-activation, while ameliorating the disruption of metabolic genes. Chromatin occupancy of GR was not predictive of Dex-regulated gene expression, contradicting the "trans-repression by tethering" model. Rather, GR activation resulted in genome-wide blockade of NF-κB interaction with chromatin and directly induced inhibitors of NF-κB and AP-1. Our investigation using GC treatments with clinically relevant timing highlights mechanisms underlying GR actions for modulating the "inflamed epigenome."
尽管糖皮质激素（GCs）已被广泛使用，但其抗炎作用的机制仍不清楚。许多研究考察了在炎症刺激之前糖皮质激素受体（GR）激活的作用。然而，临床情况是通过在炎症反应猖獗时启动GC干预来模拟的。为了表征晚期GC治疗的效果，我们在用脂多糖（LPS）刺激之前或之后用 dexamethasone（Dex）处理巨噬细胞，对其转录和染色质状态进行了分析。GR的晚期激活具有与GR预激活相似的基因表达谱，同时改善了代谢基因的破坏。GR的染色质占据情况并不能预测Dex调节的基因表达，这与“通过拴系进行反式抑制”模型相矛盾。相反，GR激活导致全基因组范围内NF-κB与染色质相互作用的阻断，并直接诱导NF-κB和AP-1的抑制剂。我们使用具有临床相关时间的GC治疗进行的研究突出了GR调节“炎症表观基因组”作用的潜在机制。
