MiR-146a potentially promotes IVIg-mediated inhibition of TLR4 signaling in LPS-activated human monocytes

Immunol Lett. 2017 May:185:64-73. doi: 10.1016/j.imlet.2017.02.015. Epub 2017 Mar 10.

Abstract

IVIg is used as an immunomodulatory agent in inflammatory disorders such as sepsis. IVIg also affects monocyte differentiation and functions, two processes in which microRNAs play a crucial role. Monocytes detect microorganisms through pathogen recognition receptors (PRRs) such as TLR4. MiR-146a has been shown to supress NF-κB and IRF3 activity, two key components of TLR4 signaling. To evaluate whether miR-146a is involved in the anti-inflammatory effects of IVIg, monocytes were treated with LPS or IVIg alone or, alternately, first activated with LPS followed by washing and addition of IVIg. MiR-146a, IRF3, TNF-α, IL-1β, IL-6, IL-10, IFN-β, TGF-β1 and IL-1Ra expression was analyzed by qPCR, while IRAK1, TRAF6 and IκBα expression was measured by Western blotting. We found that addition of IVIg to LPS-activated monocytes significantly upregulated the expression of miR-146a, which was associated with a significant reduction in the expression of its targets IRF3 and its regulated gene IFN-β. Furthermore, expression of IRAK1, TRAF6, and consequently NF-κB activation, was also reduced in LPS-activated monocytes following addition of IVIg, whereas TGF-β1, IL-10 and IL-1Ra were increased. Our results thus suggest that miR-146a is a mediator of IVIg effects in inflammatory disorders, point to an important role for miR-146a in the control of inflammation during sepsis and highlight a new mechanism by which IVIg exerts its anti-inflammatory effects in sepsis.

Keywords: IFN-β; IVIg; MiR-146a; Monocytes; Sepsis.

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Cells, Cultured
  • Cytokines / metabolism
  • Humans
  • Immunoglobulins, Intravenous / pharmacology*
  • Interferon Regulatory Factor-3 / metabolism
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides / immunology
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Monocytes / drug effects
  • Monocytes / immunology*
  • NF-kappa B / metabolism
  • Sepsis / immunology*
  • Sepsis / therapy
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • IRF3 protein, human
  • Immunoglobulins, Intravenous
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • MIRN146 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • TLR4 protein, human
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human
  • Toll-Like Receptor 4
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases