MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells

PLoS One. 2015 Dec 4;10(12):e0144295. doi: 10.1371/journal.pone.0144295. eCollection 2015.

Abstract

MicroRNA-122 (miR-122) is one of the most abundant miRs in the liver. Previous studies have demonstrated that miR-122 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the space of Disse. Here, we showed that the transient inhibition of PKR-activating protein (PACT) expression, by miR-122 or siRNA targeting of PACT, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and IL-1β, in human HSC LX-2. Sequence and functional analyses confirmed that miR-122 directly targeted the 3'-untranslated region of PACT. Immunofluorescence analysis revealed that miR-122 blocked NF-κB-nuclear translocation in LX-2 cells. We also showed that conditioned medium from miR-122-transfected LX-2 cells suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that miR-122 may downregulate cytokine production in HSCs and macrophage chemotaxis and that the targeting of miR-122 may have therapeutic potential for preventing the progression of liver diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Chemotaxis / genetics
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Macrophages / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • Cytokines
  • MIRN122 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • PRKRA protein, human
  • RNA-Binding Proteins

Grants and funding

This work was supported by a KAKEN Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (20345002 to TK) (https://kaken.nii.ac.jp/d/r/20345002.ja.html), and by a grant from Chugai (J09KF00234 to TK and OY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.