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Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Interleukin (IL)-17-producing CD4+ T cells (Th17) have been shown to play crucial roles in the pathogenesis of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF). However, the mechanism underlying the enhanced Th17 responses in these patients remains elusive. In this study, the relevance of the IL-6/signal transducer and activator of transcription 3 (STAT3)/mammalian target of rapamycin (mTOR)/Th17 loop in HBV-associated ACLF was investigated.

Methods

Eight patients with HBV-associated ACLF, eight asymptomatic chronic HBV carriers and eight healthy controls were enrolled in our study. The frequency of peripheral Th17 cells was determined by flow cytometry. IL-17 and IL-6 mRNA levels in peripheral blood mononuclear cells were quantified using quantitative real-time reverse polymerase chain reaction. The activation of STAT3 was seen upon stimulation with IL-6. Rapamycin, an mTOR inhibitor, was used for analysis of the suppressive effect on the Th17 response in vitro.

Results

The percentage of peripheral Th17 cells significantly increased in ACLF patients. CD4+ T cells from ACLF patients produced higher levels of IL-17 and IL-6 upon stimulation in vitro. Activation of STAT3 in response to IL-6 was elevated in ACLF patients. The IL-6-induced upregulation of IL-17 production by CD4+ T cells could be reversed by an mTOR inhibitor through decreasing STAT3 activation.

Conclusions

STAT3 activation upon IL-6 stimulation contributed to the enhanced Th17 response in HBV-associated ACLF patients and mTOR regulated STAT3 phosphorylation. mTOR can be a novel target to suppress Th17-mediated liver injury in HBV-associated ACLF patients.

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Abbreviations

HBV:

Hepatitis B virus

ACLF:

Acute-on-chronic liver failure

Th17:

T-helper 17 cells

IL:

Interleukin

STAT3:

Signal transducer and activator of transcription 3

mTOR:

Mammalian target of rapamycin

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Acknowledgments

This research was supported by grants from the Korea Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (grant number A092258),; from the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (Grant Number 2012049783) and from the Korean Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (grant number A102065). We thank Eun Sun Jung for technological support for the immunohistochemistry examination.

Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Jong Young Choi.

Additional information

M.-L. Cho and J. Y. Choi contributed equally to this work.

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Kim, H.Y., Jhun, J.Y., Cho, ML. et al. Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure. J Gastroenterol 49, 1264–1273 (2014). https://doi.org/10.1007/s00535-013-0891-1

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  • DOI: https://doi.org/10.1007/s00535-013-0891-1

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