Loss of NF-kappaB 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.