Transforming growth factor β gene expression is transiently enhanced at a critical stage during liver regeneration after CCl4 treatment

J. Armendariz-Borunda, H. Katai, C. M. Jones, J. M. Seyer, Andrew Kang, Rajendra Raghow

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Transforming growth factor β1 (TGFβ1) gene expression is increased in CCl4-injured rat livers. The biologic link of this increase and liver regeneration has not been established. EXPERIMENTAL DESIGN: To explore the identity of the TGFβ1-producing cells in the CCl4 regenerating liver, we hybridized untreated and CCl4-treated liver sections of TGFβ1-specific riboprobes and immunolocalized TGFβ1 protein, simultaneously. To assess the dynamics of cellular proliferation during hepatic regeneration, chronologic changes in the cellular DNA synthesis were also monitored by [3H]thymidine incorporation and autoradiography. In situ hybridization analyses were further extended by subfractionation of nonparenchymal cells into Kupffer cells/macrophages, endothelial and Ito cells, and determining TGFβ1 mRNA levels in different cell types. Finally, we experimentally tested if the temporal relationship between the transient elevation of expression of TGFβ1 and hepatic cell proliferation were casually related. RESULTS: We observed that the rate of DNA synthesis was the highest around 36 hours posttreatment and preceded the time of enhanced accumulation of TGFβ1 transcripts and protein, both of which peaked at ~48 hours and declined thereafter. Transient upregulation of TGFβ1 gene expression was seen in the inflammatory cell infiltrates around the central vein and at less extent, in portal tracts, and in perisinusoidal cells near the zone of necrosis. Like TGFβ1 transcripts, TGFβ1 protein was also predominantly co-localized in and around the pericentral and periportal cells. Kupffer cells, that accumulate abundantly in the liver 48 hours after CCl4 administration, were the primary producers of TGFβ1. The injection of neutralizing anti-TGFβ1 antibodies into animals prevented both the decline in [3H]thymidine incorporation and cell division in the waning phases of hepatic regeneration at 72 hours. CONCLUSIONS: Based on our observations that (i) TGFβ1 gene expression is triggered transiently during a crucial phase of liver regeneration, (ii) the exogenously added TGFβ1 inhibits hepatic DNA synthesis and that (iii) the administration of TGFβ1 antibodies extends the proliferative response of the regenerating liver, we conclude that TGFβ1 plays a pivotal role in down regulating liver regeneration.

Original languageEnglish (US)
Pages (from-to)283-294
Number of pages12
JournalLaboratory Investigation
Volume69
Issue number3
StatePublished - Jan 1 1993

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Liver Regeneration
Transforming Growth Factors
Gene Expression
Liver
Kupffer Cells
Thymidine
Regeneration
DNA
Cell Proliferation
Hepatic Stellate Cells
Proteins
Antibodies
Autoradiography

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Transforming growth factor β gene expression is transiently enhanced at a critical stage during liver regeneration after CCl4 treatment. / Armendariz-Borunda, J.; Katai, H.; Jones, C. M.; Seyer, J. M.; Kang, Andrew; Raghow, Rajendra.

In: Laboratory Investigation, Vol. 69, No. 3, 01.01.1993, p. 283-294.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Transforming growth factor β1 (TGFβ1) gene expression is increased in CCl4-injured rat livers. The biologic link of this increase and liver regeneration has not been established. EXPERIMENTAL DESIGN: To explore the identity of the TGFβ1-producing cells in the CCl4 regenerating liver, we hybridized untreated and CCl4-treated liver sections of TGFβ1-specific riboprobes and immunolocalized TGFβ1 protein, simultaneously. To assess the dynamics of cellular proliferation during hepatic regeneration, chronologic changes in the cellular DNA synthesis were also monitored by [3H]thymidine incorporation and autoradiography. In situ hybridization analyses were further extended by subfractionation of nonparenchymal cells into Kupffer cells/macrophages, endothelial and Ito cells, and determining TGFβ1 mRNA levels in different cell types. Finally, we experimentally tested if the temporal relationship between the transient elevation of expression of TGFβ1 and hepatic cell proliferation were casually related. RESULTS: We observed that the rate of DNA synthesis was the highest around 36 hours posttreatment and preceded the time of enhanced accumulation of TGFβ1 transcripts and protein, both of which peaked at ~48 hours and declined thereafter. Transient upregulation of TGFβ1 gene expression was seen in the inflammatory cell infiltrates around the central vein and at less extent, in portal tracts, and in perisinusoidal cells near the zone of necrosis. Like TGFβ1 transcripts, TGFβ1 protein was also predominantly co-localized in and around the pericentral and periportal cells. Kupffer cells, that accumulate abundantly in the liver 48 hours after CCl4 administration, were the primary producers of TGFβ1. The injection of neutralizing anti-TGFβ1 antibodies into animals prevented both the decline in [3H]thymidine incorporation and cell division in the waning phases of hepatic regeneration at 72 hours. CONCLUSIONS: Based on our observations that (i) TGFβ1 gene expression is triggered transiently during a crucial phase of liver regeneration, (ii) the exogenously added TGFβ1 inhibits hepatic DNA synthesis and that (iii) the administration of TGFβ1 antibodies extends the proliferative response of the regenerating liver, we conclude that TGFβ1 plays a pivotal role in down regulating liver regeneration.",
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AU - Kang, Andrew

AU - Raghow, Rajendra

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N2 - BACKGROUND: Transforming growth factor β1 (TGFβ1) gene expression is increased in CCl4-injured rat livers. The biologic link of this increase and liver regeneration has not been established. EXPERIMENTAL DESIGN: To explore the identity of the TGFβ1-producing cells in the CCl4 regenerating liver, we hybridized untreated and CCl4-treated liver sections of TGFβ1-specific riboprobes and immunolocalized TGFβ1 protein, simultaneously. To assess the dynamics of cellular proliferation during hepatic regeneration, chronologic changes in the cellular DNA synthesis were also monitored by [3H]thymidine incorporation and autoradiography. In situ hybridization analyses were further extended by subfractionation of nonparenchymal cells into Kupffer cells/macrophages, endothelial and Ito cells, and determining TGFβ1 mRNA levels in different cell types. Finally, we experimentally tested if the temporal relationship between the transient elevation of expression of TGFβ1 and hepatic cell proliferation were casually related. RESULTS: We observed that the rate of DNA synthesis was the highest around 36 hours posttreatment and preceded the time of enhanced accumulation of TGFβ1 transcripts and protein, both of which peaked at ~48 hours and declined thereafter. Transient upregulation of TGFβ1 gene expression was seen in the inflammatory cell infiltrates around the central vein and at less extent, in portal tracts, and in perisinusoidal cells near the zone of necrosis. Like TGFβ1 transcripts, TGFβ1 protein was also predominantly co-localized in and around the pericentral and periportal cells. Kupffer cells, that accumulate abundantly in the liver 48 hours after CCl4 administration, were the primary producers of TGFβ1. The injection of neutralizing anti-TGFβ1 antibodies into animals prevented both the decline in [3H]thymidine incorporation and cell division in the waning phases of hepatic regeneration at 72 hours. CONCLUSIONS: Based on our observations that (i) TGFβ1 gene expression is triggered transiently during a crucial phase of liver regeneration, (ii) the exogenously added TGFβ1 inhibits hepatic DNA synthesis and that (iii) the administration of TGFβ1 antibodies extends the proliferative response of the regenerating liver, we conclude that TGFβ1 plays a pivotal role in down regulating liver regeneration.

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