Role of Monocyte Chemoattractant Protein (MCP)-1 During Priming Phase of Liver Regeneration
Dr. Kristen Mitchell
Liver regeneration is a complex process in which cytokines and growth factors stimulate hepatocyte prolfieration. During the early “priming” phase of liver regeneration, important cytokines include interleukin (IL)-6, which is produced by activated macrophages in the liver. IL-6 binds to a receptor on hepatocytes, which leads to phosphorylation of signal transducer and activator of transcription (Stat)-3 protein. Phosphorylated Stat3 dimerizes, translocates to the nucleus and induces transcription of genes required for hepatocyte cell cycle progression. We recently found that liver regeneration is impaired in the absence of monocyte chemoattractant protein (MCP)-1, which is a proinflammatory chemokine that recruits monocytes/macrophages to areas of injury. The goal of this study was to determine if macrophage activation and Stat-3 activation are also suppressed in the absence of MCP-1. To test this, wild type and MCP-1 knockout mice were subjected to 70% partial hepatectomy to stimulate liver regeneration. Remnant liver tissue was 1) formalin-fixed for immunohistochemistry to measure expression of F4/80, a marker of macrophage activation; 2) homogenized for western blot analysis to measure expression of cell cycle proteins, Stat3 and phosphorylated Stat3; and 3) used to isolate RNA to measure levels of IL-6 transcript. Results indicate that there was no change in F4/80 staining in the liver of wild type and MCP-1 knockout mice, and IL-6 transcript was not detected in the regenerating liver. Moreover, levels of phosphorylated Stat3 were not diminished in MCP-1 knockout mice. Collectively, these findings do not support our hypothesis that MCP-1 is required to activate macrophages to produce IL-6 and activate Stat3. Future studies will determine how MCP-1 activates other non-parenchymal cells during liver regeneration to determine why this chemokine is required for optimal regeneration.