Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China.
Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu, China.
J Cell Mol Med. 2020 Jun;24(11):6008-6014. doi: 10.1111/jcmm.15108. Epub 2020 Apr 19.
Liver fibrosis is a serious chronic disease that developed by a coordinated interplay of many cell types, but the underlying signal transduction in individual cell type remains to be characterized. Nuclear factor-κB (NF-κB) is a widely accepted central player in the development of hepatic fibrosis. However, the precise role of each member of NF-κB in different cell type is unclear. Here, we generated a mouse model (Relb ) with hepatocyte-specific deletion of RelB, a member of NF-κB family. Relb mice born normally and appear normal without obvious abnormality. However, in the CCl4-induced liver fibrosis, Relb mice developed less severe disease compared with wide-type (WT) mice. The denaturation and necrosis of hepatocytes as well as the formation of false lobules in Relb mice were significantly reduced compared with WT mice. The production of α-SMA and the level of collagen I and Collagen III were greatly reduced in Relb mice comparing with WT mice. Furthermore, in patients with liver fibrosis, RelB is up-regulated along with the stage of diseases. Consistently, CCl4 treatment could up-regulate the expression of RelB as well as inflammatory cytokines such as IL-6 and TGF-β1 in hepatoma cell as well as in WT mice. Knockdown the expression of RelB in hepatoma cells greatly reduced the expression of CCl4-induced inflammatory cytokines. In summary, we provide the genetic evidence to demonstrate the critical and hepatocellular role of RelB in liver fibrosis. RelB is an important transcription factor to drive the expression of inflammatory cytokines in the initiation phase of injury.
肝纤维化是一种严重的慢性疾病，由多种细胞类型协调相互作用而发展，但个别细胞类型的潜在信号转导仍有待阐明。核因子-κB（NF-κB）是肝纤维化发生的一个被广泛接受的核心调控因子。然而，NF-κB 家族的每个成员在不同细胞类型中的确切作用尚不清楚。在这里，我们构建了一种小鼠模型（Relb），其肝细胞中特异性缺失 Relb，即 NF-κB 家族的一个成员。Relb 小鼠正常出生，外观正常，没有明显异常。然而，在 CCl4 诱导的肝纤维化中，与野生型（WT）小鼠相比，Relb 小鼠的疾病发展较轻。与 WT 小鼠相比，Relb 小鼠的肝细胞变性坏死和假小叶形成明显减少。α-SMA 的产生以及 Collagen I 和 Collagen III 的水平在 Relb 小鼠中与 WT 小鼠相比大大降低。此外，在肝纤维化患者中，Relb 的表达随着疾病的阶段而升高。一致地，CCl4 处理可上调 RelB 的表达以及炎性细胞因子，如白细胞介素 6（IL-6）和转化生长因子-β1（TGF-β1）在肝癌细胞以及 WT 小鼠中的表达。在肝癌细胞中敲低 RelB 的表达可显著降低 CCl4 诱导的炎性细胞因子的表达。总之，我们提供了遗传证据，证明了 RelB 在肝纤维化中具有关键的和肝细胞的作用。RelB 是一个重要的转录因子，可在损伤起始阶段驱动炎性细胞因子的表达。
