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

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      Abstract

      The nuclear interferon-inducible-16 (IFI16) protein acts as DNA sensor in inflammasome signaling and as viral restriction factor. Following Herpesvirus infection or UV-B treatment, IFI16 delocalizes from the nucleus to the cytoplasm and is eventually released into the extracellular milieu. Recently, our group has demonstrated the occurrence of IFI16 in sera of systemic-autoimmune patients that hampers biological activity of endothelia through high-affinity membrane binding. As a continuation, we studied the activity of endotoxin-free recombinant IFI16 (rIFI16) protein on primary endothelial cells. rIFI16 caused dose/time-dependent upregulation of IL-6, IL-8, CCL2, CCL5, CCL20, ICAM1, VCAM1, and TLR4, while secretion of IL-6 and IL-8 was amplified with lipopolysaccharide synergy. Overall, cytokine secretion was completely inhibited in MyD88-silenced cells and partially by TLR4-neutralizing antibodies. By screening downstream signaling pathways, we found that IFI16 activates p38, p44/42 MAP kinases, and NF-kB. In particular, activation of p38 is an early event required for subsequent p44/42 MAP kinases activity and cytokine induction indicating a key role of this kinase in IFI16 signaling. Altogether, our data conclude that extracellular IFI16 protein alone or by synergy with lipopolysaccharide acts like Damage-associated molecular patterns propagating "Danger Signal" through MyD88-dependent TLR-pathway.

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      Affiliations
      [1 ] 1 Department of Translational Medicine, University of Eastern Piedmont , Novara, Italy .
      [2 ] 2 Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) , Novara, Italy .
      [3 ] 3 Division of Rheumatology, Department of Medicine, University of Wisconsin-Madison , Wisconsin.
      [4 ] 4 Department of Public Health and Pediatric Sciences, University of Turin , Medical School, Turin, Italy .
      Journal
      J. Interferon Cytokine Res.
      Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
      1557-7465
      1079-9907
      Jun 2015
      : 35
      : 6
      25715050
      10.1089/jir.2014.0168
      4490711

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