Liu Liang Ming, Liang Dong Yu, Ye Chang Gen, Tu Wen Juan, Zhu Tong
Department of Hepatology, Songjiang Hospital Affiliated to the First People's Hospital Shanghai Jiaotong University, Shanghai, China.
PLoS One. 2015 Mar 24;10(3):e0121383. doi: 10.1371/journal.pone.0121383. eCollection 2015.
The urotensin II (UII)/UII receptor (UT) system is closely related to immune inflammation. In acute liver failure (ALF), the UII/UT system can promote the production and release of proinflammatory cytokines, inducing an inflammatory injury response in liver tissue. However, the mechanism by which the hepatic UII/UT system promotes proinflammatory cytokine production and release is not clear. To solve this problem, we used primary Kupffer cells (KCs) as the model system in the current study. The results showed that after lipopolysaccharide (LPS) stimulation, KCs showed significantly increased expression and release of UII/UT and proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Pretreatment with urantide, which is a UT receptor antagonist, significantly inhibited the LPS-stimulated expression and release of UII/UT, TNF-α, and IL-1β by KCs. In addition, LPS stimulation induced nuclear p38 mitogen-activated protein kinase (MAPK) protein phosphorylation and expression of the nuclear nuclear factor κB (NF-κB) p65 subunit in KCs and enhanced the binding activity of NF-κB to DNA molecules, whereas urantide pretreatment significantly inhibited the LPS-stimulated nuclear expression and activity of these molecules in KCs. Therefore, our conclusion is that the UII/UT system mediates LPS-stimulated production and release of proinflammatory cytokine by KCs, and this mediating effect at least partially relies on the inflammatory signaling pathway molecules p38 MAPK and NF-κB.
尾加压素 II（UII）/尾加压素 II 受体（UT）系统与免疫炎症密切相关。在急性肝衰竭（ALF）中，UII/UT 系统可促进促炎细胞因子的产生和释放，诱导肝组织发生炎症损伤反应。然而，肝脏 UII/UT 系统促进促炎细胞因子产生和释放的机制尚不清楚。为解决这一问题，我们在本研究中使用原代库普弗细胞（KC）作为模型系统。结果显示，脂多糖（LPS）刺激后，KC 中 UII/UT 以及促炎细胞因子肿瘤坏死因子α（TNF-α）和白细胞介素 1β（IL-1β）的表达和释放显著增加。用 UT 受体拮抗剂尿活性肽预处理可显著抑制 LPS 刺激的 KC 中 UII/UT、TNF-α和 IL-1β的表达和释放。此外，LPS 刺激可诱导 KC 中核 p38 丝裂原活化蛋白激酶（MAPK）蛋白磷酸化以及核因子κB（NF-κB）p65 亚基的表达，并增强 NF-κB 与 DNA 分子的结合活性，而尿活性肽预处理可显著抑制 LPS 刺激的 KC 中这些分子的核表达和活性。因此，我们的结论是，UII/UT 系统介导 LPS 刺激的 KC 促炎细胞因子的产生和释放，且这种介导作用至少部分依赖于炎症信号通路分子 p38 MAPK 和 NF-κB。
