The role of Kupffer cells in liver regeneration.

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.