Cytokines derived from innate lymphoid cells assist Helicobacter hepaticus to aggravate hepatocellular tumorigenesis in viral transgenic mice

Gut Pathogens

Junqing Han¹  Tianren Huang²  Xiao Han² 

[1] 0000 0004 1769 9639, grid.460018.b, Department of Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong University, 324# Jingwu Road, 250021, Jinan, China;0000 0004 1798 2653, grid.256607.0, Department of Experiment, Tumor Hospital Affiliated to Guangxi Medical University, 71# Hedi Road, 530021, Nanning, China;

关键词: Helicobacter hepaticus;    Hepatitis B virus;    Hepatocellular carcinoma;    Innate lymphoid cells;    IFN-γ/p-STAT1 axis;   

DOI  :  10.1186/s13099-019-0302-0

来源: publisher

【 摘 要 】

BackgroundRecently, intestinal microbiome has been involved in hepatic diseases due to the immunologic and metabolic communication between liver and intestine. Initiation of hepatocellular carcinoma (HCC) frequently attributes to conspiracy between immune cells and infectious carcinogens. Here, the hypothesis that the tumorigenesis of HCC with HBV infection will be aggravated by specific intestinal bacteria was verified in viral transgenic mouse models.MethodsComparative 16S rRNA sequencing was adopted to observe the intestinal enrichment of Helicobacter hepaticus in HCC. Oral administration of Helicobacter hepaticus was carried out to evaluate its hepatic carcinogenic effect in HBV transgenic mice or wildtype C57BL/6. The livers of experimental mice were collected and examined for the degree of tumorigenesis.ResultsWe found that Helicobacter hepaticus more likely colonized at lower colon of HBV-infected mice with HCC, compared with C57BL/6 and HBV-infected mice without neoplasm. Pretreatment of Helicobacter hepaticus in transgenic mice aggravated tumor formation, with higher incidence, more tumor nodule and higher serum AFP. Then, a cytokines expression patterns with inclined IFN-γ, IFN-γR1, IL-17 and IL-23 was found in HBV-infected mice with Helicobacter hepaticus. Furthermore, innate lymphoid cells, especially Th17 and NK cells which can secret IL-17 and IFN-γ respectively, might be recruited by Helicobacter hepaticus cooperated with HBV. Besides, increased expression of CD69, NKG2D and IFN-γ showed activation of cytokine production in intrahepatic NK cells. Finally, IFN-γ decreased E-cadherin expression through p-STAT1 pathway, resulting in epithelial–mesenchymal transition with inclined expression of Snail2, SIP1 and CXCR4 in vitro. p-STAT1 inhibitor was able to reverse the expression of E-cadherin and EMT resulted from IFN-γ function on HBsAg-positive hepatocytes.ConclusionsHelicobacter hepaticus generate a detrimental immune microenvironment by IFN-γ/p-STAT1 axis which can promote the tumorigenesis of hepatitis B via recruiting innate lymphoid cells.

【 授权许可】

CC BY