RelB promotes liver fibrosis via inducing the release of injury-associated inflammatory cytokines.

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 (RelbΔhep ) with hepatocyte-specific deletion of RelB, a member of NF-κB family. RelbΔhep mice born normally and appear normal without obvious abnormality. However, in the CCl4-induced liver fibrosis, RelbΔhep 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 RelbΔhep 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 RelbΔhep 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.