title: Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure.
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.
authors.affiliation: Division 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.
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kim
authors.forename: Joo Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Jong Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Jae Kyeong
authors.initials: JK
authors.lastname: Byun
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
authors.forename: Si Hyun
authors.initials: SH
authors.lastname: Bae
authors.forename: Byung Ha
authors.initials: BH
authors.lastname: Chung
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000235:genetics / Q000821:virology*; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D019694:Hepatitis B, Chronic / Q000150:complications*; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus