Induction of RelB participates in endotoxin tolerance
Induction of RelB participates in endotoxin tolerance
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DOI：
10.4049/jimmunol.177.6.4080
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发表时间：
2006-09-15
影响因子：
4.4
通讯作者：
McCall, Charles E.
中科院分区：
文献类型：
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作者：
Yoza, Barbara K.;Hu, Jean Y. -Q.;McCall, Charles E.
使用模拟脓毒症白细胞表型的THP-1人前单核细胞内毒素耐受模型，我们先前表明耐受细胞对LPS内毒素保持响应，胞质溶胶中I κ B降解，核转位和p50和p65 NF-κ B转录因子积累。尽管如此，内毒素诱导的NF-κ B依赖性先天免疫基因，如IL-1 β，在耐受表型中保持转录无反应，与脓毒症患者中观察到的内毒素耐受相似。在这项研究中，我们研究了这一矛盾，并发现，RO B，NF-κ B B家族的另一个成员，在建立耐受性诱导。ReIB表达与IL-1 β抑制相关，与正常对照组相比，脓毒症患者显示ROB增加。ROB的瞬时表达抑制内毒素应答细胞中的IL-1 β。在相反的实验中，小的抑制性RNA降低了耐受细胞中的ROB表达，并恢复了IL-1 β的内毒素诱导。当我们检查耐受细胞提取物时，我们发现了转录失活的NF-κ B p65/ReIB异二聚体。综上所述，我们的研究结果表明，ROB可以抑制促炎基因的表达，并表明脓毒症患者血液白细胞中的ReIB表达可能在内毒素耐受表型中发挥作用。
Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of I kappa B in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-kappa B transcription factors. Despite this, endotoxin-inducible NF-kappa B-dependent innate immunity genes, like IL-1 beta, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that ROB, another member of the NF-kappa B family, is induced during the establishment of tolerance. ReIB expression correlated with IL-1 beta repression, and sepsis patients showed increased ROB when compared with normal controls. Transient expression of ROB inhibited IL-1 beta in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased ROB expression in tolerant cells and restored endotoxin induction of IL-1 beta. When we examined tolerant cell extracts, we found transcriptionally inactive NF-kappa B p65/ReIB heterodimers. Taken together, our findings demonstrate that ROB can repress proinflammatory gene expression, and suggest that ReIB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.