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Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration.

ABSTRACT: A tight link has been established between inflammation and cancer. Liver regeneration is a widely used model to study the correlation between inflammation and proliferation. IL-6 is essentially involved in liver regeneration and in cancer. Recently, IL-17A has been shown to regulate not only inflammation, but also cell proliferation. Here, we analyze the role played by IL-17A signaling in liver regeneration by comparing cell proliferation in Wild Type and IL-17RA^-/- mice. Partial hepatectomy experiments performed in IL-17RA^-/- mice showed a delay in expression of early-genes to prime the residual hepatocyte to proliferate, with subsequent delay in G₁/S-phase transition. We demonstrated that IL-17RA regulates, by recruitment of non-parenchymal cell, the expression of IL-6, which in turn triggers the proliferation of residual hepatocytes. Our data indicate an important role played by IL-17RA in liver proliferation via IL-6.

SUBMITTER: Piobbico D

PROVIDER: S-EPMC6342078 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration.

Piobbico Danilo D Bartoli Daniela D Pieroni Stefania S De Luca Antonella A Castelli Marilena M Romani Luigina L Servillo Giuseppe G Della-Fazia Maria Agnese MA

Cell cycle (Georgetown, Tex.) 20181111 21-22

A tight link has been established between inflammation and cancer. Liver regeneration is a widely used model to study the correlation between inflammation and proliferation. IL-6 is essentially involved in liver regeneration and in cancer. Recently, IL-17A has been shown to regulate not only inflammation, but also cell proliferation. Here, we analyze the role played by IL-17A signaling in liver regeneration by comparing cell proliferation in Wild Type and IL-17RA<sup>-/-</sup> mice. Partial hepa ...[more]

PMID: 30395772

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Project description:BACKGROUND & AIMS:Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGF?, since TGF? signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. METHODS:Wild-type mice underwent 70% partial hepatectomy (PH); TGF? expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72?h after PH. To determine the role of Yap1 in regulating TGF? signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice. RESULTS:TGF? expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1?1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. CONCLUSION:Interactions between the TGF? and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGF?-enriched microenvironment and regenerate injured livers. LAY SUMMARY:The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.

Dataset Information

Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration.

Publications

Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration.

Similar Datasets

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