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Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease
UMass Metabolic Network Publications
  • Shashi Bala, University of Massachusetts Medical School
  • Timea Csak, University of Massachusetts Medical School
  • Karen Kodys, University of Massachusetts Medical School
  • Donna Catalano, University of Massachusetts Medical School
  • Aditya Ambade, University of Massachusetts Medical School
  • Istvan Furi, University of Massachusetts Medical School
  • Patrick Lowe, University of Massachusetts Medical School
  • Yeonhee Cho, University of Massachusetts Medical School
  • Arvin Iracheta-Vellve, University of Massachusetts Medical School
  • Gyongyi Szabo, University of Massachusetts Medical School
UMMS Affiliation
Department of Medicine, Division of Gastroenterology; Graduate School of Biomedical Sciences, Translational Science Program; UMass Metabolic Network
Publication Date
8-1-2017
Document Type
Article
Abstract

Inflammation promotes the progression of alcoholic liver disease. Alcohol sensitizes KCs to gut-derived endotoxin (LPS); however, signaling pathways that perpetuate inflammation in alcoholic liver disease are only partially understood. We found that chronic alcohol feeding in mice induced miR-155, an inflammatory miRNA in isolated KCs. We hypothesized that miR-155 might increase the responsiveness of KCs to LPS via targeting the negative regulators of LPS signaling. Our results revealed that KCs that were isolated from alcohol-fed mice showed a decrease in IRAK-M, SHIP1, and PU.1, and an increase in TNF-alpha levels. This was specific to KCs, as no significant differences were observed in these genes in hepatocytes. We found a causal effect of miR-155 deficiency on LPS responsiveness, as KCs that were isolated from miR-155 KO mice showed a greater induction of IRAK-M, SHIP1, and suppressor of cytokine signaling 1 after LPS treatment. C/EBPbeta, a validated miR-155 target, stimulates IL-10 transcription. We found a higher induction of C/EBPbeta and IL-10 in KCs that were isolated from miR-155 KO mice after LPS treatment. Gain- and loss-of-function studies affirmed that alcohol-induced miR-155 directly regulates IRAK-M, SHIP1, suppressor of cytokine signaling 1, and C/EBPbeta, as miR-155 inhibition increased and miR-155 overexpression decreased these genes in LPS or alcohol-pretreated wild-type KCs. HDAC11, a regulator of IL-10, was significantly increased and IL-10 was decreased in KCs that were isolated from alcohol-fed mice. Functionally, knockdown of HDAC11 with small interfering RNA resulted in an IL-10 increase in LPS or alcohol-pretreated Mvarphi. We found that acetaldehyde and NF-kappaB pathways regulate HDAC11 levels. Collectively, our results indicate that the alcohol-induced responsiveness of KCs to LPS, in part, is governed by miR-155 and HDAC11.

Keywords
  • HDAC11,
  • IRAK-M,
  • MyD88,
  • TNF-α,
  • miR-155
DOI of Published Version
10.1189/jlb.3A0716-310R
Source
J Leukoc Biol. 2017 Aug;102(2):487-498. doi: 10.1189/jlb.3A0716-310R. Epub 2017 Jun 5. Link to article on publisher's site
Related Resources
Link to Article in PubMed
PubMed ID
28584078
Citation Information
Shashi Bala, Timea Csak, Karen Kodys, Donna Catalano, et al.. "Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease" Vol. 102 Iss. 2 (2017) ISSN: 0741-5400 (Linking)
Available at: http://works.bepress.com/gyongyi_szabo/215/