Department of Emergency and Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China.
Mol Med Rep. 2018 Dec;18(6):5775-5783. doi: 10.3892/mmr.2018.9559. Epub 2018 Oct 16.
Sepsis is characterized by systemic inflammatory responses. In the present study, the role of deleted in liver cancer 1 (DILC), interleukin (IL)‑6, signal transducer and activator of transcription 3 (STAT3), and Toll‑like receptor 4 (TLR4) in the pathogenesis of sepsis was investigated. Reverse transcription‑quantitative polymerase chain reaction analysis and western blotting were performed to evaluate the effects of lipopolysaccharide (LPS) on the expression of DILC, IL‑6, STAT3, and TLR4, in addition to the effects of DILC and IL‑6 on the synthesis of tumor necrosis factor (TNF‑α), chemokine ligand 5 (CCL5), E‑selectin and C‑X‑C motif chemokine receptor 1 (CXCR1). In addition, the regulatory association between DILC, IL‑6, STAT3 and TLR4 was investigated. LPS reduced the expression level of DILC, and enhanced the expression of IL‑6, STAT3 and TLR4. DILC directly and negatively regulated the synthesis of IL‑6, as demonstrated by the markedly decreased luciferase activity in cells transfected with a wild‑type DILC plasmid. On the other hand, compared with the scramble control, DILC and IL‑6 small interfering (si)RNAs significantly suppressed the expression of IL‑6, STAT3 and TLR4. In addition, DILC siRNA enhanced the expression of IL‑6, STAT3 and TLR4, whereas the expression levels of TNF‑α, CCL5, E‑selectin and CXCR1 in LPS‑treated THP‑1 cells were downregulated following transfection with DILC and IL‑6 siRNAs. In patients with sepsis, DILC expression was inhibited, although the expression levels of IL‑6, STAT3 and TLR4 were upregulated. In addition, the expression levels of TNF‑α, CCL5, E‑selectin and CXCR1 in patients with sepsis were higher compared with normal subjects. Therefore, DILC may mediate the crosstalk between the cascades of IL‑6/STAT3 and TNF‑α signaling, indicating that DILC may act as a prognostic biomarker of sepsis, and may serve as a potential therapeutic target for the treatment of sepsis.
脓毒症的特征是全身炎症反应。在本研究中，研究了缺失肝癌 1（DILC）、白细胞介素（IL）-6、信号转导和转录激活因子 3（STAT3）和 Toll 样受体 4（TLR4）在脓毒症发病机制中的作用。采用逆转录-定量聚合酶链反应分析和蛋白质印迹法评估脂多糖（LPS）对 DILC、IL-6、STAT3 和 TLR4 表达的影响，以及 DILC 和 IL-6 对肿瘤坏死因子（TNF-α）、趋化因子配体 5（CCL5）、E-选择素和 C-X-C 基序趋化因子受体 1（CXCR1）合成的影响。此外，还研究了 DILC、IL-6、STAT3 和 TLR4 之间的调节关联。LPS 降低了 DILC 的表达水平，并增强了 IL-6、STAT3 和 TLR4 的表达。DILC 直接负调控 IL-6 的合成，这是通过转染野生型 DILC 质粒的细胞中荧光素酶活性明显降低来证明的。另一方面，与 scramble 对照相比，DILC 和 IL-6 小干扰（si）RNA 显著抑制了 IL-6、STAT3 和 TLR4 的表达。此外，DILC siRNA 增强了 IL-6、STAT3 和 TLR4 的表达，而 LPS 处理的 THP-1 细胞中转染 DILC 和 IL-6 siRNA 后，TNF-α、CCL5、E-选择素和 CXCR1 的表达水平下调。在脓毒症患者中，DILC 的表达受到抑制，尽管 IL-6、STAT3 和 TLR4 的表达水平上调。此外，与正常受试者相比，脓毒症患者 TNF-α、CCL5、E-选择素和 CXCR1 的表达水平更高。因此，DILC 可能介导 IL-6/STAT3 和 TNF-α 信号通路级联反应之间的串扰，表明 DILC 可能作为脓毒症的预后生物标志物，并可能作为脓毒症治疗的潜在治疗靶点。
