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

• DOI: 10.1007/s00535-013-0891-1
• Publication Date: 2013-12-24T04:17:59Z
• Authors: Hee Yeon Kim; Joo Yeon Jhun; Mi-La Cho; Jong Young Choi; Jae Kyeong Byun; Eun-Kyung Kim; Seung Kew Yoon; Si Hyun Bae; Byung Ha Chung; Chul Woo Yang
• Keywords: Adult; Male; STAT3 Transcription Factor; Sirolimus; 0301 basic medicine; Interleukin-6; TOR Serine-Threonine Kinases; Interleukin-17; Acute-On-Chronic Liver Failure; Middle Aged; Flow Cytometry; Real-Time Polymerase Chain Reaction; Up-Regulation; 3. Good health; 03 medical and health sciences; Hepatitis B, Chronic; Case-Control Studies; Leukocytes, Mononuclear; Humans; Th17 Cells; Female; Prospective Studies; Phosphorylation

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.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.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.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.