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IRF5 and IRF8 modulate the CAL-1 human plasmacytoid dendritic cell line response following TLR9 ligation

Folkert Steinhagen1,2, Luis G Rodriguez1, Debra Tross1

  • 1Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

European Journal of Immunology
|November 29, 2015
PubMed

Insights

Interferon regulatory factor 5 (IRF5) upregulates CpG-induced gene expression in plasmacytoid dendritic cells (pDCs), while IRF8 inhibits this process by blocking IRF5 activity. These opposing transcription factors control Toll-like receptor 9 signaling in pDCs.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • CpG-containing oligonucleotides (ODNs) activate human plasmacytoid dendritic cells (pDCs), leading to type-1 interferon and cytokine production.
  • Interferon regulatory factors (IRFs) are critical mediators of CpG-induced pDC activation.

Purpose of the Study:

  • To investigate the opposing roles of IRF5 and IRF8 in regulating CpG-dependent gene expression in human pDCs.
  • To elucidate the mechanism by which IRF8 influences TLR9 signaling pathways.

Main Methods:

  • Utilized the human CAL-1 pDC cell line, which mimics primary pDCs.
  • Employed RNA interference and microarray analysis to assess gene expression changes.
  • Applied proximity ligation assay to study protein interactions and localization.

Main Results:

  • IRF5 was found to upregulate Toll-like receptor 9 (TLR9)-driven gene expression.
  • IRF8 demonstrated a downregulation of the same TLR9-dependent genes.
  • IRF8's inhibitory effect was dependent on the presence of IRF5, and they were observed to colocalize and cotranslocate upon CpG stimulation.

Conclusions:

  • IRF5 and IRF8 possess opposing functions in controlling TLR9 signaling in human pDCs.
  • IRF8 inhibits TLR9-dependent gene expression by directly interfering with IRF5 activity.
  • The interplay between IRF5 and IRF8 is crucial for regulating pDC responses to CpG ODNs.

Keywords:
CpG oligonucleotideDendritic cellIRF8, IRF5TLR9

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