be favored over the other by altering the redox environment of the protein. Polymerization of PAI-2 occurs spontaneously under physiological conditions, for instance in the cytosol of placental cells. Cytosolic PAI-2 tends to be monomeric, while PAI-2 in secretory organelles (which tend to be more oxidizing than the cytosol) is more prone to polymerization. For these combined reasons, it is thought that PAI-2 may sense and respond to environmental redox potential. Mechanism PAI-2 uses a suicide inhibition mechanism (a common mechanism for serpins) to irreversibly inactivate tissue plasminogen activator and urokinase. First, the target serine protease docks to PAI-2 and catalyzes cleavage of the RCL, between residues Arg-380 and Thr-381. At this point, two outcomes are possible: the protease escapes, leaving an inactive PAI-2; or the protease forms a permanent, covalently-bonded complex with PAI-2, in which the protease is significantly distorted. Biological Functions Although extracellular (glycosylated) PAI-2 functions to regulate fibrinolysis, it remains unclear whether this inhibitory role is the main function of PAI-2. PAI-2 is predominantly intracellular. The secretory signal peptide of PAI-2 is relatively inefficient, perhaps by evolutionary design, as various mutations to the signal sequence can significantly enhance secretion efficiency. PAI-2 is undetectable in adult plasma, and is typically only detectable during pregnancy, in myelomonocytic leukemias, or in gingival crevicular fluid; moreover, PAI-2 is a slower inhibitor than its counterpart PAI-1 by orders of magnitude (based on second order rate constants). On the other hand, detailed intracellular roles for PAI-2 have not yet been conclusively established. PAI-2 is upregulated during both pregnancy and immune responses. During pregnancy, PAI-2 is particularly present in the decidua and amniotic fluid, where it may protect membranes from digestion and aid in remodeling fetal and uterine tissues. PAI-2 assists PAI-1 in regulating fibrinolysis and may help prevent overexpression of PAI-1, which increases risk of thrombosis. Over the course of a pregnancy, PAI-2 plasma concentration rises from nearly-undetectable levels to 250 ng/mL (mostly in glycosylated form). Among immune cells, macrophages are the main producers of PAI-2, as both B-cells and T-cells do not produce significant amounts. PAI-2 plays a role in inflammatory responses and infections, potentially in downregulating T cells that secrete IgG2c and interferon type II. Due to its position on chromosome 18 close to the bcl-2 protooncogene and several other serpins, PAI-2's role in apoptosis has been investigated, but current evidence remains inconclusive. A recent study suggests PAI-2 may be a