Chen Xiaoping, Yoza Barbara K, El Gazzar Mohamed, Hu Jean Y Q, Cousart Sue L, McCall Charles E
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Clin Vaccine Immunol. 2009 Jan;16(1):104-10. doi: 10.1128/CVI.00320-08. Epub 2008 Nov 19.
Transcription factors and chromatin structural modifiers induce clinically relevant epigenetic modifications of blood leukocytes during severe systemic inflammation (SSI) in humans and animals. These changes affect genes with distinct functions, as exemplified by the silencing of a set of acute proinflammatory genes and the sustained expression of a group of antimicrobial and anti-inflammatory genes. This paradigm is closely mimicked in the THP-1 human promonocyte cell model of lipopolysaccharide (LPS) endotoxin tolerance. We previously reported that LPS-induced de novo expression of RelB is required for generating tolerance to interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) expression. RelB represses transcription by binding with heterochromatic protein 1 alpha (HP1alpha) to the proximal promoters of IL-1beta and TNF-alpha. In contrast, we report herein that RelB is required for sustained expression of anti-inflammatory IkappaBalpha in LPS-tolerant THP-1 cells. RelB transcription activation requires binding to the IkappaBalpha proximal promoter along with NF-kappaB p50 and is associated with an apparent dimer exchange with p65. We also observed that RelB induced during human SSI binds to the IkappaBalpha proximal promoter of circulating leukocytes. We conclude that RelB functions as a dual transcription regulator during LPS tolerance and human SSI by activating and repressing innate immunity genes.
在人类和动物的严重全身炎症（SSI）期间，转录因子和染色质结构修饰因子会诱导血液白细胞发生与临床相关的表观遗传修饰。这些变化会影响具有不同功能的基因，例如一组急性促炎基因的沉默以及一组抗菌和抗炎基因的持续表达。在脂多糖（LPS）内毒素耐受的THP-1人原单核细胞模型中，这一模式得到了密切模拟。我们之前报道过，LPS诱导的RelB从头表达是产生对白介素-1β（IL-1β）和肿瘤坏死因子α（TNF-α）表达耐受性所必需的。RelB通过与异染色质蛋白1α（HP1α）结合至IL-1β和TNF-α的近端启动子来抑制转录。相比之下，我们在此报道，RelB是LPS耐受的THP-1细胞中抗炎性IkappaBα持续表达所必需的。RelB转录激活需要与NF-κB p50一起结合至IkappaBα近端启动子，并且与与p65的明显二聚体交换有关。我们还观察到，在人类SSI期间诱导产生的RelB会结合至循环白细胞的IkappaBα近端启动子。我们得出结论，RelB在LPS耐受和人类SSI期间通过激活和抑制先天免疫基因发挥双重转录调节因子的作用。
