Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor

Abstract

The protein Z (PZ)-dependent plasma protease inhibitor (ZPI) is a glycoprotein that inhibits factor XIa and, in the presence of PZ, FXa. Recently, ZPI has been shown to be an acute-phase protein (APP). As usually APPs downregulate the harmful effects of inflammation, we tested whether ZPI could modulate the increase of cytokines observed in inflammatory states. We observed that recombinant human ZPI (rhZPI) significantly decreases the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor- α (TNF-α) induced by lipopolysaccharide (LPS) in a whole blood model. This inhibitory effect was unaffected by the presence of PZ or heparin. A ZPI mutant within the reactive loop center ZPI (Y387A), lacking anticoagulant activity, still had an anti-inflammatory activity. Surprisingly, rhZPI did not inhibit the synthesis of IL-6 or TNF-α when purified monocytes were stimulated by LPS, whereas the inhibitory effect was evidenced when lymphocytes were added to monocytes. The requirement of lymphocytes could be due to the synthesis of CCL5 (RANTES), a chemokine mainly produced by activated lymphocytes which is induced by rhZPI, and which can reduce the production of proinflammatory cytokines in whole blood. Lastly, we observed that the intraperitoneal injection of rhZPI significantly decreased LPS-induced IL-6 and TNF-α production in mouse plasma.

Plasma Proteomics Elucidated a Protein Signature in COVID-19 Patients with Comorbidities and Early-Diagnosis Biomarkers

“…Noteworthily, two acute-phase reactants, CBG and ZPI, showed lower levels in patients in the COVID-19 studies. Both proteins play a role in reducing the harmful effects of inflammation [16,17]. The reduced plasma levels of CBG in COVID-19 patients have not been previously reported.…”

“…Similarly, the acute phase response protein ZPI was reduced in CPs compared to HCs. ZPI is increased in the acute phase response and promotes a reduction in the levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) [16,45]. Recently, Toomer et al showed that ZPI is increased in moderate and severe COVID-19 patients compared to healthy controls by ELISA [46].…”

Impact of COVID-19 on Subclinical Placental Thrombosis and Maternal Thrombotic Factors

“…The ZPI/Z ratio can be used as a marker of inflammation because of the excess of production of ZPI in inflammation [ 14 ]. In our study, the ZPI/Z ratio was significantly increased in newborns of the recovered group compared to the control group.…”

“…An altered plasma PZ concentration is also associated with adverse pregnancy outcomes (miscarriage, stillbirth, intra uterine growth restriction and preeclampsia) [ 10 , 11 , 12 , 13 ]. Furthermore, ZPI has an anti-inflammatory role, and there is a major increase in the level of ZPI in response to inflammation [ 14 ]. As a result, an increased ratio of ZPI/Z suggests an inflammatory state.…”

Proteomic analysis of extracellular vesicle cargoes mirror the cardioprotective effects of rivaroxaban in patients with venous thromboembolism

“…Besides their anticoagulant effects, PROS1, SEPRINA10, and PROZ can also potentiate anti-inflammatory signaling. For instance, SER-PINA10 was recently identified to function as an acute phase protein [47] and subsequently shown to downregulate the expression of proinflammatory cytokines (TNFα, IL-1β, IL-6, and CCL3) independent of its anticoagulant effects [48], however, the underlying mechanism remain to be characterized. In line with these findings, low…”