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J Gastroenterol. 2014 Aug;49(8):1264-73. doi: 10.1007/s00535-013-0891-1. Epub 2013 Dec 25.

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

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  • 1Division of Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-040, Korea.

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.

PMID:
24366287
[PubMed - indexed for MEDLINE]
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