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The Extracellular IFI16 Protein Propagates Inflammation in Endothelial Cells Via p38 MAPK and NF-κB p65 Activation

Mandar Bawadekar1,2,3, Marco De Andrea4, Irene Lo Cigno1,2

  • 11 Department of Translational Medicine, University of Eastern Piedmont , Novara, Italy .

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|February 26, 2015
PubMed

Insights

Extracellular interferon-inducible-16 (IFI16) protein acts as a danger signal, activating endothelial cells via the MyD88-dependent TLR pathway. This finding sheds light on autoimmune diseases and inflammatory responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The nuclear interferon-inducible-16 (IFI16) protein is involved in inflammasome signaling and viral restriction.
  • IFI16 can be released extracellularly following infection or UV-B treatment and is found in the sera of autoimmune patients.
  • Extracellular IFI16 has been shown to impair endothelial cell function.

Purpose of the Study:

  • To investigate the effects of endotoxin-free recombinant IFI16 (rIFI16) on primary endothelial cells.
  • To elucidate the signaling pathways activated by extracellular IFI16.
  • To determine the role of IFI16 in propagating danger signals.

Main Methods:

  • Treatment of primary endothelial cells with rIFI16.
  • Measurement of cytokine and chemokine upregulation (IL-6, IL-8, CCL2, CCL5, CCL20).
  • Assessment of adhesion molecule and TLR4 expression.
  • Analysis of downstream signaling pathways (MAP kinases, NF-kB) and inhibition studies (MyD88 silencing, TLR4 neutralization).

Main Results:

  • rIFI16 induced dose/time-dependent upregulation of IL-6, IL-8, CCL2, CCL5, CCL20, ICAM1, VCAM1, and TLR4.
  • Synergistic amplification of IL-6 and IL-8 secretion was observed with lipopolysaccharide.
  • Cytokine secretion was dependent on MyD88 and partially on TLR4.
  • IFI16 activated p38, p44/42 MAP kinases, and NF-kB, with p38 activation being an early event crucial for downstream signaling.

Conclusions:

  • Extracellular IFI16 acts as a Damage-associated molecular pattern (DAMP), propagating a "Danger Signal".
  • IFI16 signaling occurs through the MyD88-dependent Toll-like receptor (TLR) pathway.
  • IFI16, alone or synergistically with LPS, contributes to inflammatory responses in endothelial cells.

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