The Role of Kupffer Cells in Liver Regeneration.

Abstract

The liver has a remarkable proliferative capacity after a partial hepatectomy. Previous studies have indicated that Kupffer cells have the potential to exert both stimulatory and inhibitory influences on hepatocyte proliferation. To elucidate the role of Kupffer cells in liver regeneration, mice were selectively depleted of Kupffer cells by injection of liposome-encapsulated dichloromethylene diphosphonate (lipo-MDP) at day 3 after a two-thirds hepatectomy. Results showed that liver regeneration was delayed after Kupffer cell-depletion. In control mice, hepatocyte growth factor (HGF) mRNA expressions were enhanced during liver regeneration and expressions of HGF were localized in fat-storing cells (Ito cells). In Kupffer cell-depleted mice, the number of HGF-expressing cells decreased in the regenerating liver, and expressions of HGF and its receptor (c-met) as well as other growth factors/cytokines were less prominent than in control mice. In contrast, expressions of TNF-alpha, another potent cytokine involved in liver regeneration, did not differ between Kupffer cell-depleted and control mice during the regeneration. Administration of TNF-alpha antibody did not reduce the expression of HGF or liver regeneration. These findings imply that Kupffer cells play a stimulatory role in liver regeneration by enhancing HGF expression via TNF-alpha-non-mediated mechanisms.

Hepatocyte Growth Factor/Scatter Factor and MET Are Involved in Arterial Repair and Atherogenesis

“…56,57 Interestingly, HGF/SF expression by liver macrophages is essential for a full regenerative response of hepatocytes after injury. 58 We propose that a similar course of events occurs in the arterial wall where HGF/SF is expressed in macrophage-derived foam cells in atherosclerotic lesions of apoE Ϫ/Ϫ mice ( Figure 5, d and e) and MET is expressed in neighboring SMCs ( Figure 5, f and g). Expression of HGF/SF has also been reported in macrophages in human arterial lesions.…”

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

“…However, the messages for the chemoattractants MCP-1 and GRO were increased in the regenerating liver by 30 and 90 min after PHx, respectively. These chemokines can recruit monocytes͞ macrophages, which have the potential to exert both stimulatory and inhibitory influences on hepatocyte proliferation (53), in the liver after PHx (54). MCP-1 and GRO also may play a role in angiogenesis and tissue remodeling (55).…”

APCs in the Liver and Spleen Recruit Activated Allogeneic CD8+ T Cells to Elicit Hepatic Graft-Versus-Host Disease

“…These data imply that the primary role of liver APCs in the development of GVHD may be as a cellular magnet, attracting activated allogeneic T cells specific for host tissue Ags. Although there is still a controversy as to whether hepatic APCs might themselves be capable of inducing the allo-specific responses (39,40), it is clear that activated Kupffer cells can produce high levels of IL-6, TNF-␣ (41)(42)(43)(44)(45)(46), and chemokines such as MIP1␣ (15). Thus, hepatic macrophages could direct the trafficking of activated allogeneic CD8 ϩ T cells into the liver by the means of the chemokines secreted either by hepatic macrophages themselves or by other cells in the liver via the proinflammatory stimulation of macrophage-derived IL-6 and TNF-␣, leading to hepatic GVHD.…”