Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy

Abstract

Kupffer cells (KCs) are located in the liver sinusoids adjacent to hepatocytes and are capable of producing important growth-regulating mediators that exert both stimulatory and inhibitory influences on hepatocyte proliferation by paracrine mechanisms. To elucidate the overall effect of KC depletion on liver regeneration, mice were selectively and long-standing depleted of KCs by liposome-encapsulated dichloromethylene diphosphonate. Using in vivo fluorescence microscopy, immunohistochemistry, Western blot analysis, and NF-kappaB transcription factor DNA binding activity and cytokine assays, we analyzed livers of KC-depleted and KC-competent mice at days 3, 5, and 8 after partial (i.e., 68%) hepatectomy (PH). Selective KC elimination delayed cell proliferation, as indicated by significantly reduced PCNA and cyclin B1 protein expression in liver tissue at day 3 after PH. This was associated with a lower liver weight at day 8 upon PH. Resection-associated activation of NF-kappaB with translocation into parenchymal and nonparenchymal cell nuclei was diminished in livers of KC-depleted mice, primarily at day 3 after PH. KC-depleted mice further lacked the resection-induced rise in TNF-alpha and IL-6 serum concentrations. These findings imply that KCs play a stimulatory role in liver regeneration, mainly by activating NF-kappaB with influence on the cell cycle and by enhancing expression of the proliferative cytokines TNF-alpha and IL-6.

Hepatoprotective Effects of Sedum sarmentosum on D-Galactosamine/Lipopolysaccharide–Induced Murine Fulminant Hepatic Failure

“…TLR4 signaling initiates systemic inflammation by producing several cytokines. Moreover, it is well known that expression of these molecules is controlled by transcription factors including NF-κB (38). D-GalN blocks the transcriptional activity of NF-κB, which is concomitantly activated by TNF-α, and suppresses the apoptotic effects of the latter (39).…”

Novel functions of platelets in the liver

“…Kupffer cell-depleted mice fail to exhibit increases in TNF-α and IL-6 to levels that are equivalent to those in mice with Kupffer cells after hepatectomy. 61 The interrelationship between platelets and Kupffer cells has been well studied using ischemia/reperfusion models. A triangular interaction among platelets, Kupffer cells, and leukocytes has been demonstrated as the major mechanism of injury.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Hepatic steatosis is a predisposing factor to TNF-␣-induced cell death (Diehl, 2005). Nonetheless, KC function was found to be essential for hepatocellular proliferation and crucial in liver regeneration (Malik et al, 2002;Bilzer et al, 2006;Abshagen et al, 2007). In particular, hepatocyte growth factor as well as the cytokines IL-6 (Aldeguer et al, 2002) and TNF-␣ (Kirillova et al, 1999;Abshagen et al, 2007) provided by Kupffer cells and endothelial cells stimulate hepatocyte proliferation by triggering hepatocytic DNA replication via NF-〉 (Seto et al, 1998;Armbrust et al, 2002;Bruun et al, 2002;Lalani et al, 2005;Bastard et al, 2006;Wang et al, 2006a;Simons et al, 2007).…”

“…Nonetheless, KC function was found to be essential for hepatocellular proliferation and crucial in liver regeneration (Malik et al, 2002;Bilzer et al, 2006;Abshagen et al, 2007). In particular, hepatocyte growth factor as well as the cytokines IL-6 (Aldeguer et al, 2002) and TNF-␣ (Kirillova et al, 1999;Abshagen et al, 2007) provided by Kupffer cells and endothelial cells stimulate hepatocyte proliferation by triggering hepatocytic DNA replication via NF-〉 (Seto et al, 1998;Armbrust et al, 2002;Bruun et al, 2002;Lalani et al, 2005;Bastard et al, 2006;Wang et al, 2006a;Simons et al, 2007). In addition, Kupffer cells seem to be involved in maintenance of adequate perfusion during liver cell proliferation-a function that could be related to Kupffer cell-derived cytokines or Kupffer cell-mediated effects on nitric oxide metabolism, which apparently plays an important role in hepatic microcirculation, particularly after liver injury (Rolfe et al, 1997;West et al, 1999;Holden et al, 2000;Meijer et al, 2000, Abshagen et al, 2008Palmes et al, 2005;Schuett et al, 2007).…”