TNFα-induced hepatocyte apoptosis is associated with alterations of the cell cycle and decreased stem loop binding protein

Black, Dalliah M.; Bird, Mark A.; Hayden, Melissa A.; Schrum, Laura W.; Lange, P; Samson, Charles M.; Hatano, Etsuro; Rippe, Richard A.; Brenner, David A.; Behrns, Kevin E.

doi:10.1016/j.surg.2003.11.004

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…However, it has been reported that inhibition of NF-B results in a significant decrease in the number of mitotic figures in the regenerating liver without impairment of DNA synthesis (6). Because of this finding and the present results of decreased cyclin B1 expression in KC-depleted mice, we suppose a NF-B-dependent alteration of the cell cycle at the S-to-G 2 /M phase transition.…”

Section: Discussionsupporting

confidence: 64%

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

Abshagen¹,

Eipel²,

Kalff³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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Section: Discussionsupporting

confidence: 64%

“…Upon nuclear translocation, NF-B induces the transcription of a large set of immediate-early genes (20,34), which are particularly involved in the cell cycle regulation (6). Moreover, NF-B is responsible for the expression of numerous proinflammatory mediators, including TNF-␣ (6,20).…”

Section: Discussionmentioning

confidence: 99%

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

Abshagen¹,

Eipel²,

Kalff³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Most proteins that shuttle between the nucleus and the cytoplasm contain NLSs and/or NESs. NLSs are essential to drive nuclear import of relatively large proteins (28). Under normal conditions, COMMD1 is detectable in the nucleus, but the localization of COMMD1 is predominantly cytoplasmic in most cell types (2,7,8) (Figure 1, unpublished results).…”

Section: Discussionmentioning

confidence: 92%

Nuclear‐Cytosolic Transport of COMMD1 Regulates NF‐κB and HIF‐1 Activity

Müller

Sluis

Groot

et al. 2009

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Copper metabolism MURR1 domain1 (COMMD1) is a novel inhibitor of the transcription factors NF-κB and HIF-1, which play important roles in inflammation and tumor growth, respectively. In this study, we identified two highly conserved nuclear export signals (NESs) in COMMD1 and revealed that these NESs were essential and sufficient to induce maximal nuclear export of COMMD1. Inhibition of CRM1-mediated nuclear export by Leptomycin B resulted in nuclear accumulation of COMMD1. In addition, low oxygen concentrations induced the active export of COMMD1 from the nucleus in a CRM1-dependent manner. Disruption of the NESs in COMMD1 increased the repression of COMMD1 in transcriptional activity of NF-κB and HIF-1. In conclusion, these data indicate that COMMD1 undergoes constitutive nucleocytoplasmic transport as a novel mechanism to regulate NF-κB and HIF-1 signaling.

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“…While TGF-b is a potent inhibitor of hepatocyte DNA synthesis (Black et al, 2004), TNF-a, IL-6, and IL-1b have been shown to exert both positive and negative Fig. 8.…”

Section: Expression Of Cytokinesmentioning

confidence: 99%

Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Thirunavukkarasu

Uemura

Wang

et al. 2005

Journal Cellular Physiology

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Endotoxin is implicated in the pathology of acute liver failure. The mechanisms of its actions on quiescent hepatic stellate cells (qHSCs) and their implications in hepatocyte injury are incompletely understood. We investigated effects of endotoxin (bacterial lipopolysaccharide; LPS) on qHSCs and subsequently on hepatocytes. After overnight culture following their isolation, qHSCs were incubated with or without endotoxin for 24 h. The cells and the culture supernatant were analyzed for cytokines and nitric oxide (NO) synthesis. The effects of qHSC-conditioned media on hepatocytes were then determined. LPS increased inducible NO synthase expression, stimulated NO synthesis, and inhibited DNA synthesis in qHSCs. qHSC-conditioned medium inhibited DNA synthesis in hepatocytes without affecting NO synthesis, while LPS (1-1,000 ng/ml)-conditioned qHSC medium stimulated NO synthesis and caused further inhibition of DNA synthesis and apoptosis. These effects of LPS were more pronounced when qHSCs were incubated with serum, but not with LPS-binding protein (LBP) although CD14 (a receptor for LPS-LBP complex) was found in qHSCs. LPS stimulated the synthesis of TNF-alpha, interleukin (IL)-6, and IL-1beta but not of TGF-beta in qHSCs. Individually or together, L-N(G)-monomethylarginine and antibodies to IL-1beta, IL-6, and TNF-alpha only partly reversed qHSC + LPS-conditioned medium-induced inhibition of DNA synthesis in hepatocytes. These results suggest that the effects of LPS on qHSCs are novel, occurring without the aid of LBP/CD14. They also indicate that other factors, in addition to NO, TGF-beta, TNF-alpha, IL-1beta, and IL-6 are involved in the mechanisms of the growth inhibitory effects of qHSCs on hepatocytes.

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TNFα-induced hepatocyte apoptosis is associated with alterations of the cell cycle and decreased stem loop binding protein

Cited by 10 publications

References 34 publications

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 hepatectomy

Nuclear‐Cytosolic Transport of COMMD1 Regulates NF‐κB and HIF‐1 Activity

Normal rat hepatic stellate cells respond to endotoxin in LBP‐independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

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