Department of Surgery, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
Cytokine. 2011 Feb;53(2):145-52. doi: 10.1016/j.cyto.2010.10.007.
The clinical phenotype in sepsis that is observed as LPS tolerance is determined by silencing of pro-inflammatory genes like IL-1 beta (IL-1β). This study shows that facultative heterochromatin (fHC) silences IL-1β expression during sepsis, where we find dephosphorylated histone H3 serine 10 and increased binding of heterochromatin protein-1 (HP-1) to the promoter. In both human sepsis blood leukocytes and an LPS tolerant human THP-1 cell model, we show that IκBα and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) function as dominant labile mediators of fHC formation at the IL-1β promoter. Protein synthesis inhibition decreases levels of IκBα and RelB, converts silent fHC to euchromatin, and restores IL-1β transcription. We further show TLR dependent NFκB p65 and histone H3 serine 10 phosphorylation binding at the promoter. We conclude that the resolution phase of sepsis, which correlates with survival in humans, may depend on the plasticity of chromatin structure as found in fHC.
在败血症中观察到的 LPS 耐受的临床表型是由促炎基因（如 IL-1β）沉默决定的。本研究表明，兼性异染色质（fHC）在败血症期间沉默 IL-1β 的表达，我们发现组蛋白 H3 丝氨酸 10 去磷酸化和异染色质蛋白-1（HP-1）与启动子的结合增加。在人类败血症血液白细胞和 LPS 耐受的人 THP-1 细胞模型中，我们表明 IκBα 和 v-rel 网状内皮增生病毒癌基因同源物 B（RelB）作为 IL-1β 启动子上 fHC 形成的主要不稳定调节剂发挥作用。蛋白质合成抑制降低 IκBα 和 RelB 的水平，将沉默的 fHC 转化为常染色质，并恢复 IL-1β 转录。我们进一步显示 TLR 依赖性 NFκB p65 和组蛋白 H3 丝氨酸 10 磷酸化结合在启动子上。我们得出结论，与人类生存相关的败血症缓解期可能取决于染色质结构的可塑性，如在 fHC 中发现的那样。
