Abstract
BackgroundLiver regeneration following 70 % partial hepatectomy (PH) requires the coordinated expression of soluble mediators produced by macrophages. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulus of monocyte recruitment and macrophage activation. The goal of this study was to determine how MCP-1 contributes to liver regeneration.MethodsPH was performed on anesthetized C57Bl/6 (wild type) and MCP-1 knockout mice, and macrophage-produced cytokines and hepatocyte proliferation were measured.ResultsIn wild type mice, hepatic MCP-1 protein levels increased 4–6 h after PH, and elevated plasma MCP-1 levels were detected 12 h after PH. Hepatocyte proliferation was comparable in MCP-1 knockout and wild type mice, as was the expression of macrophage-derived cytokines, TNFα and IL-6, and levels of phosphorylated STAT3. The number of CCR2+ cells in the liver was similar in MCP-1 knockout and wild type mice, which suggests that other chemokines may recruit CCR2+ cells in the absence of MCP-1. Studies with CCR2 knockout mice revealed that hepatocyte proliferation was suppressed ~40 % compared to wild type mice 36 h after PH, but proliferation and liver-body-weight ratios were similar at 48 h.ConclusionThese findings suggest that MCP-1 is not required for PH-induced liver regeneration, yet the role of CCR2 warrants further study.
Highlights
Liver regeneration following 70 % partial hepatectomy (PH) requires the coordinated expression of soluble mediators produced by macrophages
We investigated the possibility that the production of Kupffer cell-derived cytokines and subsequent liver regeneration are influenced by monocyte chemoattractant protein-1 (MCP-1 or CCL2), a well-known, potent stimulus of macrophage recruitment and activation [16,17,18]
Monocyte chemoattractant protein-1 (MCP-1) levels increase after PH To examine MCP-1 production after PH, MCP-1 mRNA levels were quantified in the remnant liver, and protein levels were measured in liver homogenates and plasma
Summary
Liver regeneration following 70 % partial hepatectomy (PH) requires the coordinated expression of soluble mediators produced by macrophages. Liver regeneration is a complex physiological process that is influenced by soluble mediators, including cytokines, growth factors and hormones [1]. Hepatocyte proliferation is accompanied by the activation of nonparenchymal cells in the liver, which produce cytokines and growth factors that facilitate hepatocyte cell cycle progression [1]. Liver macrophages (Kupffer cells) are important for the early priming phase of liver regeneration. Following PH, Kupffer cells become activated and produce tumor necrosis factor (TNF)-α, which functions through an autocrine pathway to activate nuclear factor kappa B (NF-kB) and stimulate interleukin (IL)-6 production. Kupffer cell-derived IL-6 acts on hepatocytes to activate the signal transducer and activator of
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