Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis

Xiaoyan Li,Yujie Su,Yuehua Huang,Zhiliang Gao,Chan Xie,Xuefeng Hua,Jing Liu,Min Zhang,Liang Zhou,Xu Li

doi:10.1186/s12967-017-1167-y

Abstract

BackgroundLiver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. However, the immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive.MethodsLiver tissues and peripheral blood were obtained simultaneously from 32 hepatitis B virus infected patients undergoing surgery for hepatocellular carcinoma at the medical center of Sun Yat-sen University. Liver tissues at least 3 cm away from the tumor site were used for the analyses. Levels of Th17 cells and regulatory T cells were detected by flow cytometry analysis and immunohistochemistry. In vitro experiment, we adopted magnetic cell sorting to investigate how hepatic stellate cells regulate the levels of Th17 cells and regulatory T cells.ResultsWe found that hepatic Th17 cells and regulatory T cells were increased in patients with advanced stage HBV-related liver fibrosis. Hepatic stellate cells upregulated the levels of Th17 cells and regulatory T cells via PGE2/EP2 and EP4 pathway.ConclusionsWe found that the increased levels of Th17 cells and regulatory T cells were upregulated by hepatic stellate cells. These results may provide insight into the role of hepatic stellate cells and Th17 cells and regulatory T cells in the persistence of fibrosis and into the occurrence of hepatocellular carcinoma following cirrhosis.

Highlights

Liver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma
These data suggest a latent mechanism in which human Hepatic stellate cells (HSC) are equipped to simultaneously upregulate the levels of Th17 cells and regulatory T cells (Tregs) via the Prostaglandin E2 (PGE2)/EP2 and EP4 pathway to affect the development of hepatitis B virus (HBV)-LF and even hepatocellular carcinoma (HCC)
We demonstrated that PGE2 secreted by LX-2 and primary HSC (pHSC) can simultaneously augment the percentages of Th17 cells and Tregs via its receptors EP2 and EP4, which is similar with previous reports [28, 51]

Summary

Introduction

Liver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. The immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive. Hepatic stellate cells (HSC) have dominated studies exploring mechanisms of liver fibrosis over the last two IL17-producing CD4+ T (Th17) cells and regulatory T cells (Tregs) have been recognized as unique subsets of effector T cells that are distinct from the Th1 and Th2. The enrichment of Tregs in the livers of patients with advanced fibrosis was found and these Tregs might enhance fibrosis by releasing IL-8 [18] Both Th17 and Tregs were enriched in tumors or marginal region of HCC and increased intratumoral IL-17-producing cell or Tregs density predicted poor prognosis in HCC patients [19,20,21]. The relationship between Th17 cells, Tregs and different stages of liver fibrosis remains elusive and further investigation is warranted and basically no research available so far to detect the effect of HSC on the status of Th17 cells as well as Tregs in HBV-related liver fibrosis (HBV-LF)

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Discussion

Conclusion