Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma

Abstract

Plasminogen activator inhibitor (PAI)-2 expression is acutely upregulated in pregnancy, inflammation, infection, and other pathophysiological conditions. Circumstances that prevent PAI-2 upregulation are associated with chronic pathology. Altogether this strongly suggests that PAI-2 is one of the many proteins that maintain homeostasis during damage or stress. However, several functions ranging from a classical serpin to various intracellular roles have been ascribed to PAI-2 and, because none of these have been definitively proven in vivo, to this day its precise role or roles remains an enigma. This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2.

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

“…PAI-2, a multifunctional protein, belongs to the SERPIN family, which inhibits serine proteases (11). PAI-2 expression in monocytes and macrophages is up-regulated rapidly, mainly through IKK/NF-κB activation, after stimulation with inflammatory mediators and pathogens (13).…”

“…Recently, PAI-2 has been associated with newly identified uPA-independent biological functions, probably through targeting an as yet uncharacterized intracellular molecule (11). In addition, PAI-2 is one of the major molecules up-regulated in macrophages in response to TLR4 activators or inflammatory mediators, suggesting its function in the regulation of innate immunity (12,13).…”

PZP and PAI-2: Structurally-diverse, functionally similar pregnancy proteins?

“…However, PAI-2 is found as a secreted high molecular weight (HMW) 60 -70 kDa glycoprotein in biological fluids including pregnancy plasma (Coolman et al, 2006). Unlike other serpins, no pathological outcomes have been linked to PAI-2 polymerization nor does PAI-2 convert to a latent inactive state in the absence of certain cofactors (Lee et al, 2011).…”

“…In humans PAI-2 is acutely upregulated, from negligible levels up to 250 ng/mL in late pregnancy (Coolman et al, 2006, Hunt et al, 2009, Guller et al, 2011. PAI-2 is expressed by numerous cell types including placental trophoblasts, endothelial cells, monocytes and macrophages, with large scale upregulation evident in vitro by a wide range of stimulants associated with inflammatory and/or fibrinolytic conditions (Lee et al, 2011).…”

“…In pregnancy extracellular PAI-2 is believed to protect against premature placental separation and maintain haemostasis by controlling localized proteolysis and tissue destruction by counteracting the activity of uPA and tPA (Lee et al, 2011). These target protease specificities are shared by plasminogen activator inhibitor type 1 (PAI-1/SERPINE1) (Lee et al, 2011), even though PAI-1 and PAI-2 are phylogeneticially distinct as denoted by their classification into different serpin clades (Silverman et al, 2004).…”