The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming

J Exp Med. 1998 Jun 1;187(11):1799-811. doi: 10.1084/jem.187.11.1799.


The serine proteinase inhibitor (serpin) plasminogen activator inhibitor type 2 (PAI-2) is well characterized as an inhibitor of extracellular urokinase-type plasminogen activator. Here we show that intracellular, but not extracellular, PAI-2 protected cells from the rapid cytopathic effects of alphavirus infection. This protection did not appear to be related to an effect on apoptosis but was associated with a PAI-2-mediated induction of constitutive low-level interferon (IFN)-alpha/beta production and IFN-stimulated gene factor 3 (ISGF3) activation, which primed the cells for rapid induction of antiviral genes. This primed phenotype was associated with a rapid development of resistance to infection by the PAI-2 transfected cells and the establishment of a persistent productive infection. PAI-2 was also induced in macrophages in response to viral RNA suggesting that PAI-2 is a virus response gene. These observations, together with the recently demonstrated PAI-2-mediated inhibition of tumor necrosis factor-alpha induced apoptosis, (a) illustrate that PAI-2 has an additional and distinct function as an intracellular regulator of signal transduction pathway(s) and (b) demonstrate a novel activity for a eukaryotic serpin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / immunology
  • Alphavirus / immunology*
  • Antiviral Agents
  • Apoptosis
  • Cytopathogenic Effect, Viral / drug effects
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation / drug effects
  • HeLa Cells
  • Humans
  • Influenza A virus / immunology
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha / genetics*
  • Interferon-alpha / immunology
  • Interferon-beta / genetics*
  • Interferon-beta / immunology
  • Plasminogen Activator Inhibitor 2 / genetics
  • Plasminogen Activator Inhibitor 2 / pharmacology*
  • Poly I-C / immunology
  • Polymerase Chain Reaction
  • Proteins / metabolism
  • RNA, Messenger
  • Ross River virus / immunology
  • Serine Proteinase Inhibitors / genetics
  • Serine Proteinase Inhibitors / pharmacology*
  • Sindbis Virus / immunology
  • Transcription Factors / metabolism
  • Viral Proteins / metabolism
  • Virus Latency


  • Antiviral Agents
  • DNA-Binding Proteins
  • IRF9 protein, human
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Plasminogen Activator Inhibitor 2
  • Proteins
  • RNA, Messenger
  • Serine Proteinase Inhibitors
  • Transcription Factors
  • Viral Proteins
  • Interferon-beta
  • Poly I-C