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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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Toll-like receptor 3-elicited MAPK activation induces stabilization of interferon-β mRNA

Ingvild Bjellmo Johnsen1, Thuy Thanh Nguyen, Bjarte Bergstrøm

  • 1Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim N-7006, Norway. ingvild.johnsen@ntnu.no

Cytokine
|December 28, 2011
PubMed

Insights

Toll-like receptor 3 (TLR3) activation stabilizes interferon-beta (IFN-β) mRNA. This stabilization involves TRIF, p38 MAPK, and MK2, enhancing IFN-β production during infections.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Cytokine overproduction can cause inflammatory diseases.
  • Adenine- and uridine-rich elements (AREs) in mRNA 3'-UTRs typically destabilize transcripts.
  • Interferon-beta (IFN-β) mRNA contains an ARE sequence.

Purpose of the Study:

  • To investigate the mechanisms of IFN-β mRNA stabilization following innate immune system activation.
  • To identify the signaling pathways involved in TLR-mediated IFN-β mRNA stabilization.

Main Methods:

  • Utilized monocyte-derived dendritic cells and cells from TRIF(-/-) and MyD88(-/-) mice.
  • Stimulated cells with Toll-like receptor (TLR) ligands: dsRNA (TLR3) and LPS (TLR4).
  • Assessed mRNA stability, protein activation (MK2), and employed chemical inhibition and siRNA knockdown.

Main Results:

  • TLR3 ligand dsRNA and TLR4 ligand LPS stabilized IFN-β mRNA.
  • dsRNA-induced stabilization was TRIF-dependent.
  • dsRNA activated MAPK-activated protein 2 (MK2) via TRIF and p38 MAPK.
  • Inhibition of p38 MAPK and MK2, or MK2 knockdown, abolished dsRNA-induced mRNA stabilization.

Conclusions:

  • TLR3 signaling pathways involving TRIF, p38 MAPK, and MK2 enhance IFN-β mRNA stability.
  • This mechanism contributes to increased IFN-β levels during pathogen infections.
  • Provides insight into the regulation of inflammatory responses.

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