Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Abstract

Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1−/−) mice demonstrated strongly elevated plasma IFN-γ concentrations after injection of either LPS or SEB. In addition, PAI-1−/− splenocytes released more IFN-γ after incubation with LPS or SEB than Wt splenocytes. Both PAI-1−/− CD4+ and CD8+ T cells produced more IFN-γ upon stimulation with SEB. LPS-induced IFN-γ release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN-γ release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN-γ release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.

Expression of Coagulation-Related Protein Genes During LPS-Induced Preterm Delivery in the Pregnant Mouse

“…30 Plasminogen activator inhibitor 1 also appears to play a role beyond inhibiting plasminogen activators, including directly inhibiting interferon g (IFNg) production. 10 Through its effects on surface protein and cellular adhesion, PAI-1 appears to function as a ''molecular switch'' that can turn entire molecular pathways, such as inflammation or thrombosis, on or off. 26,31 In septic human patients, higher blood levels of PAI-1 protein have been correlated with disease severity, increased cytokine levels, hypotension, and risk of death.…”

“…single-chain glycoprotein in the serpin gene family that is consumed in the process of inhibiting the plasminogen activators. 26 Increased PAI-1 consistently accompanies SIRS induced by sepsis or endotoxin 10,16,[24][25][26] ; thus, PAI-1 contributes to the prothrombotic state during the later stages of sepsis. 30 Plasminogen activator inhibitor 1 also appears to play a role beyond inhibiting plasminogen activators, including directly inhibiting interferon g (IFNg) production.…”

“…9 Lipopolysaccharide (LPS), derived from the bacterial cell walls of E coli, causes a pronounced SIR in animal and human tissues both in vivo and in vitro. Examples include intraperitoneal injection in transgenic and wild-type mice 10,11 and rats 12 ; intravenous injection in rats, 13 guinea pigs, 14 and sheep 15 ; and inhalation of nebulized LPS in human volunteers. 16 Multiple reports have demonstrated that the LPS-induced proinflammatory response also stimulates premature delivery in mice.…”

Plasminogen Activator Inhibitor-1 Plasma Concentration in Allergic Asthma Patients during Allergen Challenge

“…PAI-1 –/– mice sensitized to OVA and subsequently challenged with OVA had significantly attenuated IgE production and nasal hyperresponsiveness when compared with sensitized and challenged wild-type mice [5]. Interestingly, some light has recently been shed on the possible mechanisms responsible for the effects of PAS on the development of Th2-type immune response and consequently IgE synthesis [32]. In fact, endogenous PAI-1 inhibits IFN-γ release and skews the immune response towards Th2, leading to enhanced IgE production [5, 32].…”

“…Interestingly, some light has recently been shed on the possible mechanisms responsible for the effects of PAS on the development of Th2-type immune response and consequently IgE synthesis [32]. In fact, endogenous PAI-1 inhibits IFN-γ release and skews the immune response towards Th2, leading to enhanced IgE production [5, 32]. Genetically determined increased PAI-1 production in response to environmental challenge, such as that seen in patients carrying the 4G allele, may promote the development of Th2-type immune response and IgE production.…”