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

Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial... 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-κB 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-κB 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-α and IL-6 serum concentrations. These findings imply that KCs play a stimulatory role in liver regeneration, mainly by activating NF-κB with influence on the cell cycle and by enhancing expression of the proliferative cytokines TNF-α and IL-6. in vivo fluorescence microscopy; hepatocytes; clodronate; tumor necrosis factor-α; interleukin-6; proliferating cell nuclear antigen; nuclear factor-κB Address for reprint requests and other correspondence: B. Vollmar, Institute for Experimental Surgery, Univ. of Rostock, 18055 Rostock, Germany (e-mail: brigitte.vollmar@med.uni-rostock.de ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Gastrointestinal and Liver Physiology The American Physiological Society

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

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0193-1857
eISSN
1522-1547
DOI
10.1152/ajpgi.00399.2006
pmid
17322066
Publisher site
See Article on Publisher Site

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-κB 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-κB 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-α and IL-6 serum concentrations. These findings imply that KCs play a stimulatory role in liver regeneration, mainly by activating NF-κB with influence on the cell cycle and by enhancing expression of the proliferative cytokines TNF-α and IL-6. in vivo fluorescence microscopy; hepatocytes; clodronate; tumor necrosis factor-α; interleukin-6; proliferating cell nuclear antigen; nuclear factor-κB Address for reprint requests and other correspondence: B. Vollmar, Institute for Experimental Surgery, Univ. of Rostock, 18055 Rostock, Germany (e-mail: brigitte.vollmar@med.uni-rostock.de )

Journal

AJP - Gastrointestinal and Liver PhysiologyThe American Physiological Society

Published: Jun 1, 2007

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