In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway

Ledda-Columbano, Giovanna M.; Curto, Monica; Piga, Rosaria; Zedda, A I; Menegazzi, Marta; Sartori, Claudia; Shinozuka, Hisashi; Bluethmann, Horst; Poli, Valeria; Ciliberto, Gennaro; Columbano, Amedeo

doi:10.1038/sj.onc.1202018

Cited by 95 publications

(77 citation statements)

References 26 publications

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“…14 Hepatocyte proliferation induced by ligands of nuclear receptors is also TNF-a and IL-6-independent. 15 Indeed, our studies showed that the proliferative response of hepatocytes from TNFR-1 and IL-6 knockout mice to the CAR ligand TCPOBOP is similar to or higher than that of wild type mice, clearly demonstrating that these cytokines do not play a major role in nuclear receptor mediated hepatocyte proliferation. The same studies showed that hepatocyte proliferation induced by the PPARa ligand, ciprofibrate, was also TNF-a-IL-6 independent.…”

Section: Direct Hyperplasia Induced By Ligands Of Nuclear Receptorsmentioning

confidence: 88%

Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth

Columbano

Ledda-Columbano²

2003

Cell Death Differ

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Section: Direct Hyperplasia Induced By Ligands Of Nuclear Receptorsmentioning

confidence: 88%

Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth

Columbano

Ledda-Columbano²

2003

Cell Death Differ

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“…TNF and mainly IL-6 -independent pathways play a minor role in hepatocyte proliferation. 35 This pro-proliferative function for A20 in hepatocytes seems independent from its antiapoptotic properties. Analysis of cell cycle progression in vitro in nonapoptotic conditions show that hepatocytes expressing A20 demonstrate increased response to growth factors with higher number of proliferating cells and earlier entry in the cell cycle when compared to control hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Longo¹,

Patel²,

Shrikhande³

et al. 2005

Hepatology

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The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-B. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21 waf1 . In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156-164.)

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“…A number of studies suggested that cytokines may play a critical role in cell proliferation and apoptosis by peroxisome proliferators (Bojes et al, 1997;Hasmall et al, 2000a;Parzefall et al, 2001). At the same time, many reports questioned that cytokines are a requisite for altered cell turnover by peroxisome proliferators (Ledda-Columbano et al, 1998;Anderson et al, 2001). To address this controversy, this study looked at the temporal profile of expression changes related to cytokine signaling in liver.…”

Section: Gene Expression Profiling Reveals Pparα-mediated Immunosupprmentioning

confidence: 99%

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

Woods

Kosyk

Bradford

et al. 2007

Toxicology and Applied Pharmacology

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Administration of peroxisome proliferators to rodents causes proliferation of peroxisomes, induction of β-oxidation enzymes, hepatocelluar hypertrophy and hyperplasia, with chronic exposure ultimately leading to hepatocellular carcinomas. Many responses associated with peroxisome proliferators are nuclear receptor-mediated events involving peroxisome proliferators-activated receptor alpha (PPARα). A role for nuclear receptor-independent events has also been shown, with evidence of Kupffer cell-mediated free radical production, presumably through NAPDH oxidase, induction of redox-sensitive transcription factors involved in cytokine production and cytokinemediated cell replication following acute treatment with peroxisome proliferators in rodents. Recent studies have demonstrated, by using p47 phox -null mice which are deficient in NADPH oxidase, that this enzyme is not related to the phenotypic events caused by prolonged administration of peroxisome proliferators. In an effort to determine the timing of the transition from Kupffer cell-to PPARα-dependent modulation of peroxisome proliferator effects, gene expression was assessed in liver from Pparα-null, p47 phox -null and corresponding wild-type mice following treatment with 4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid (WY-14,643) for 8 h, 24 h, 72 h, 1 wk, or 4 wks. WY-14,643-induced gene expression in p47 phox -null mouse liver differed substantially from wildtype mice at acute doses and striking differences in baseline expression of immune related genes were evident. Pathway mapping of genes that respond to WY-14,643 in a time-and dose-dependent manner demonstrates suppression of immune response, cell death and signal transduction and promotion of lipid metabolism, cell cycle and DNA repair. Furthermore, these pathways were largely dependent on PPARα, not NADPH oxidase demonstrating a temporal shift in response to peroxisome proliferators. Overall, this study shows that NADPH oxidase-dependent events, while detectable following acute treatment, are transient and short-lived. To the contrary, a strong PPARα-specific gene signature was evident in mice that were continually exposed to WY-14,643.

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In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway

Cited by 95 publications

References 26 publications

Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth

Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

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