Induction of hepatocyte mitosis in intact adult rat by interleukin-1 α and interleukin-6

Koga, Mutuyosi; Ogasawara, Hayato

doi:10.1016/0024-3205(91)90139-3

Cited by 34 publications

(19 citation statements)

References 21 publications

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“…How similar initiating mechanisms can lead to different biological responses is an unresolved problem. IL-6 inhibits growth factor-induced DNA replication in cultured hepatocytes (44) but may increase hepatocyte DNA synthesis in vivo in intact, nonpartially hepatectomized animals (45). In our experiments, IL-6 injection of wild-type mice had an inhibitory effect on DNA synthesis after PH whereas it stimulated DNA replication in TNFR-I knockout mice that are deficient in hepatic IL-6 mRNA.…”

Section: Discussionmentioning

confidence: 43%

Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

Yamada

Kirillova

Peschon

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

883

800

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The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-B and STAT3 transcription factors shortly after PH failed to occur. Binding of AP-1 after PH was decreased in TNFR-I knockout mice compared with animals with the intact receptor whereas C͞EBP binding was not modified. Injection of interleukin 6 in TNFR-I-deficient animals 30 min before PH corrected the defect in DNA synthesis and restored STAT3 and AP-1 binding to normal levels but had no effect on NF-B binding in the regenerating liver. The results indicate that TNF, signaling through the TNFR-I, can initiate liver regeneration and acts by activating an interleukin 6-dependent pathway that involves the STAT3 transcription factor.

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Section: Discussionmentioning

confidence: 43%

Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

Yamada

Kirillova

Peschon

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

883

800

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“…It is conceivable that these stress responses represent priming events (32) that include the initial rapid decrease in C/EBP mRNA and that the sustained suppression of C/EBP gene transcription is associated with progression of hepatocytes through the cell cycle. In this regard, a recent study suggests that the cytokine interleukin 6 is involved in priming the hepatocytes to enter the cell cycle during liver regeneration (26). Furthermore, other studies demonstrate that injection of interleukin 6 into mice suppresses the hepatic expression of C/EBPao and activates expression of particular acute-phase proteins (24).…”

Section: Discussionmentioning

confidence: 99%

Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture.

et al. 1992

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As an approach to understanding physiological mechanisms that control the proliferation of highly differentiated cells, we are addressing whether certain hepatic transcription factors participate in mechanisms that control the growth of hepatocytes. We have focused on CCAAT enhancer-binding protein (C/EBP alpha), a transcription factor which is highly abundant in normal liver and is considered to regulate expression of many genes, including some involved in energy metabolism (S. L. McKnight, M. D. Lane, and S. Gluecksohn-Walsh. Genes Dev. 3:2021-2024, 1989). Using Northern (RNA) blot analysis, we have examined the expression of C/EBP alpha mRNA during liver regeneration and in primary cultures of hepatocytes. C/EBP alpha mRNA levels decrease 60 to 80% within 1 to 3 h after partial hepatectomy as the cells move from G0 to G1 and decrease further when cells progress into S phase. Run-on transcription analysis is in agreement with the Northern blot data, thus suggesting that C/EBP alpha is transcriptionally regulated in regenerating liver. C/EBP alpha mRNA expression also decreases dramatically during the growth of freshly isolated normal hepatocytes cultured under conventional conditions (on dried rat tail collagen; stimulated to proliferate by epidermal growth factor [EGF] and insulin). Cultures of hepatocytes on rat tail collagen in the presence or absence of EGF clearly show that within 3 h, EGF depresses C/EBP alpha mRNA expression and that this effect is substantially greater by 4 h. Inhibition of protein synthesis in the liver by cycloheximide or in cultured hepatocytes by puromycin or cycloheximide effectively blocks the down-regulation of C/EBP alpha gene expression, apparently by stabilizing the normal rapid turnover of the C/EBP alpha mRNA (half-life of <2 h). This drop in C/EBP alpha gene expression in response to activation of hepatocyte growth is consistent with the proposal that C/EBP alpha has an antiproliferative role to play in highly differentiated cells (R. M. Umek, A. D. Friedman, and S. L. McKnight, Science 251: 288-292, 1991).

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“…High levels of IL-6 were detected in the sera of the patients with alcoholic liver cirrhosis [16], hepatitis B virus infection [17,18], and acute hepatitis [19]. IL-6 also increased the numbers of platelets [20] and neutrophils [21], and hepatocyte mitosis in synergy with IL-1 [22]. Furthermore, in vitro treatment of hepatocytes with IL-6 induces the production of phospholipase A2, one of the major inflammatory mediators [23].…”

Section: Introductionmentioning

confidence: 99%

IL-6 induces hepatic inflammation and collagen synthesisin vivo

Choi¹,

Kang²,

Yang³

et al. 1994

Clinical and Experimental Immunology

102

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SUMMARY IL-6 regulates the synthesis of a broad spectrum of acute phase proteins in the liver. Also, it is involved in the pathogenesis of many fibrogenic diseases. To study the inflammatory effects of IL-6 on the liver in vivo, human rIL-6, produced in Escherichia coli, was injected intraperitoneally into rats (25 ,g/100 g body weight). The major fraction of injected IL-6 was accumulated in the liver within 40 min, and the number of platelets was increased during 72 h after injection. After 5 weeks of injection, the levels of serum glutamine pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) were not changed, but they were significantly elevated at 13 weeks of treatment. Meanwhile, serum albumin levels were slightly decreased compared with those of controls. The same phenomena were observed in carbon tetrachloride-treated rats. Collagen synthesis was increased in the liver tissues and in the culture supernatants of hepatic lipocytes isolated from the rats treated with IL-6 for 13 weeks. Histological analysis correlated well with biochemical analysis. At 5 weeks of treatment, only mild pathological changes were observed, but severe hepatocyte necrosis and the accumulation of fibres in necrotic area were developed in the liver of IL-6-treated rats after 13 weeks of treatment, confirming that hepatic inflammation and fibrosis were developed. IL-6 activities in the sera and in the culture supernatants of lipocytes from IL-6-treated rats were elevated compared with those in controls. These biochemical and pathological data indicate that IL-6 can induce hepatic inflammation, and it has important roles in the pathogenesis of fibrosis and diseases of the liver in vivo. In addition, these results will provide useful information for the clinical trials of IL-6.

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Induction of hepatocyte mitosis in intact adult rat by interleukin-1 α and interleukin-6

Cited by 34 publications

References 21 publications

Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture.

IL-6 induces hepatic inflammation and collagen synthesisin vivo

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