THE SERINE PROTEINASE-INHIBITOR (SERPIN) PLASMINOGEN ACTIVATION INHIBITOR TYPE-2 PROTECTS AGAINST VIRAL CYTOPATHIC EFFECTS BY CONSTITUTIVE INTERFERON-ALPHA BETA PRIMING/

The serine proteinase inhibitor (serpin) plasminogen activator inhibit or type 2 (PAI-2) is well characterized as an inhibitor of extracellul ar urokinase-type plasminogen activator. Here we show that intracellul ar, but not extracellular, PAI-2 protected cells from the rapid cytopa thic effects of alphavirus infection. This protection did not appear t o be related to an effect on apoptosis but was associated with a PAI-2 -mediated induction of constitutive low-level interferon (IFN)-alpha/b eta production and IFN-stimulated gene factor 3 (ISGF3) activation, wh ich primed the cells for rapid induction of antiviral genes. This prim ed phenotype was associated with a rapid development of resistance to infection by the PAI-2 transfected cells and the establishment of a pe rsistent productive infection. PAI-2 was also induced in macrophages i n response to viral RNA suggesting that PAI-2 is a virus response gene . These observations, together with the recently demonstrated PAI-2-me diated inhibition of tumor necrosis factor-or induced apoptosis, (a) i llustrate that PAI-2 has an additional and distinct function as an int racellular regulator of signal transduction pathway(s) and (b) demonst rate a novel activity for a eukaryotic serpin.