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© The Rockefeller University Press, 0022-1007/1998/6/1799/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 11, June 1, 1998 1799-1811

Articles

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

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

From the * Queensland Cancer Fund Experimental Oncology Unit and the {ddagger} EBV Unit, The Queensland Institute of Medical Research, Brisbane 4029, Australia

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}/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-{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.

Key Words: plasminogen activator inhibitor • serpin • interferon • alphavirus • Ross River virus

Address correspondence to Toni M. Antalis, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane 4029, Australia. Phone: 61-7-33620312; Fax 61-7-33620107; E-mail: toniA{at}qimr.edu.au

Abbreviations used: CAT, chloramphenicol acetyl transferase; CPE, cytopathic effect; IRF, interferon response factor; ISGF3, interferon-stimulated gene factor 3; ISRE, interferon-stimulated response element; MOI, multiplicity of infection; OAS, oligoadenylate synthetase; PAI-2, plasminogen activator inhibitor; poly IC, polyinosinic-polycytidylic acid; RRV, Ross River virus; serpin, serine proteinase inhibitor; TCID50, 50% tissue culture infectivity dose; uPA, urokinase-type plasminogen activator.


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