Skip to main content
Article thumbnail
Location of Repository

The Serine Proteinase Inhibitor (Serpin) Plasminogen Activation Inhibitor Type 2 Protects against Viral Cytopathic Effects by Constitutive Interferon α/β Priming

By Toni M. Antalis, May La Linn, Karen Donnan, Luis Mateo, Joy Gardner, Joanne L. Dickinson, Kathy Buttigieg and Andreas Suhrbier


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)-α/β 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-α 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

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (1996). A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes.
  2. (1994). A truncated form of the IRF-2 transcription factor has the properties of a postinduction repressor of interferon-beta gene expression.
  3. (1984). Action of human lymphoblastoid interferon on HeLa cells infected with RNAcontaining animal viruses.
  4. (1997). Adaptive and maladaptive mechanisms of cellular priming.
  5. (1996). An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor–induced apoptosis in U937 cells.
  6. (1996). An overview of the interferon system: signal transduction and mechanisms of action.
  7. (1996). Antibody dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis.
  8. (1997). Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors.
  9. (1996). Autocrine amplification of type I interferon gene expression mediated by interferon stimulated gene factor 3 (ISGF3).
  10. (1995). Biological and clinical aspects of plasminogen activator inhibitor type 2.
  11. (1985). Cell to cell transmission of the “priming” effect on the induction of human fibroblast interferon.
  12. (1995). Characterisation of specific DNA-binding factors activated by double stranded RNA as positive regulators of interferon a/b–stimulated genes.
  13. (1994). Cleaved intracellular plasminogen activator inhibitor 2 in human myeloleukaemia cells is a marker of apoptosis.
  14. (1988). Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor.
  15. (1992). Constitutive expression of an ISGF2/IRF1 transgene leads to interferon-independent activation of interferon-inducible genes and resistance to virus infection.
  16. (1992). Control of plasminogen-activator inhibitor type 2 gene expression in the differentiation of monocytic cells.
  17. (1993). Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene.
  18. (1995). Deficient signaling in mice devoid of double-stranded RNAdependent protein kinase.
  19. (1995). Delay of vaccinia virus–induced apoptosis in nonpermissive Chinese hamster ovary cells by the cowpox virus CHOhr and adenovirus E1B 19K genes.
  20. (1989). Effects of adriamycin and etoposide on the replication of adenovirus 5 in sensitive and resistant human tumour cells.
  21. (1988). Establishment of a human cell line (MonoMac6) with characteristics of mature monocytes.
  22. Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon alpha.
  23. (1994). Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells.
  24. Gene induction by interferons: functional complementation between trans-acting factors induced by alpha interferon and gamma interferon.
  25. (1993). Identification and analysis of all components of a gel retardation assay by combination with immunoblotting.
  26. (1995). Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes.
  27. (1993). Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells.
  28. (1991). Isolation of intact nuclei from hematopoietic cell types. Nucleic Acids Res.
  29. (1994). Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.
  30. (1979). Mechanisms of persistent infections by cytopathic viruses in tissue culture.
  31. Molecular cloning and sequence of partial cDNA for interferon-induced (29–59) oligo(A) synthetase mRNA from human cells.
  32. (1985). Multiplecloning-site plasmids for the rapid construction of recombinant poxviruses.
  33. (1986). Normal human epidermis contains an interferon-like protein.
  34. (1994). Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile.
  35. Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes.
  36. (1987). Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester–mediated differentiation of U-937 human histiocytic lymphoma cells.
  37. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha–induced apoptosis. Evidence for an alternate biological function.
  38. (1995). Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4.
  39. (1995). Plasminogen activator inhibitor type 2: an intracellular keratinocyte differentiation product that is incorporated into the cornified envelope. Exp. Cell Res.
  40. (1996). Production of plasminogen activator and plasminogen activator inhibitors by alveolar macrophages in control subjects and AIDS patients.
  41. (1996). Protease inhibitor 6 cannot be secreted, which suggests it’s a new type of cellular serpin.
  42. (1991). Protection from tumour necrosis factor–mediated cytolysis by overexpression of plasminogen activator inhibitor type-2.
  43. Recombinant Sindbis virus as an expression system for cell biology.
  44. (1992). Regulation of plas-1811 Antalis et al. minogen activation inhibitor mRNA levels in lipopolysaccharide-stimulated human monocytes. Correlation with production of the protein.
  45. (1979). Replication of standard and defective Ross River virus in BHK cells: patterns of viral RNA and polypeptide synthesis.
  46. (1995). Reversal of the interferon-sensitive phenotype of a vaccinia virus lacking E3L by expression of the reovirus S4 gene.
  47. (1992). Role of protein phosphorylation in activation of interferon-stimulated gene factors.
  48. Southwestern blot mapping of potential regulatory proteins binding to the DNA encoding plasminogen activator inhibitor type 2.
  49. (1989). Stimulation of plasminogen activator inhibitor activity in human monocytes infected with dengue virus.
  50. (1996). Suppression of TNF-a–induced apoptosis by NF-kB.
  51. (1997). Target protease specificity of the viral serpin CrmA. Analysis of five caspases.
  52. (1994). The alphaviruses: gene expression, replication, and evolution.
  53. (1994). The beta-interferon promoter responds to priming through multiple independent regulatory elements.
  54. (1991). The efficiency of the uncleaved secretion signal in the plasminogen activator inhibitor type 2 protein can be enhanced by point mutations that increase its hydrophobicity.
  55. (1993). The ovalbumin family of serpin proteins.
  56. (1995). Thiol agents and Bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of the transcription factor NF-kB.
  57. (1995). Transcriptional induction by double stranded RNA is mediated by interferon-stimulated gene factor 3.
  58. (1995). Tumour necrosis factor–alpha is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization.
  59. (1997). Vaccinia virus serpin B13R (SPI-2) inhibits1810 Plasminogen Activation Inhibitor Type 2 Induces IFN-a/b interleukin-1b–converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1b–induced fever.
  60. (1992). Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1b converting enzyme.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.