Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0041-1730037
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor
![](https://www.thieme-connect.de/media/10.1055-s-00033990/202102/lookinside/thumbnails/10-1055-s-0041-1730037_210020-1.jpg)
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.
Keywords
protein Z-dependent plasma protease inhibitor - proinflammatory cytokines - CCL5 - lipopolysaccharide - monocytesPublication History
Received: 28 September 2020
Accepted: 08 April 2021
Article published online:
25 June 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Han X, Huang ZF, Fiehler R, Broze Jr GJ. The protein Z-dependent protease inhibitor is a serpin. Biochemistry 1999; 38 (34) 11073-11078
- 2 Han X, Fiehler R, Broze Jr GJ. Characterization of the protein Z-dependent protease inhibitor. Blood 2000; 96 (09) 3049-3055
- 3 Tabatabai A, Fiehler R, Broze Jr GJ. Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor. Thromb Haemost 2001; 85 (04) 655-660
- 4 Girard TJ, Lasky NM, Tuley EA, Broze Jr GJ. Protein Z, protein Z-dependent protease inhibitor (serpinA10), and the acute-phase response. J Thromb Haemost 2013; 11 (02) 375-378
- 5 Zhang J, Tu Y, Lu L, Lasky N, Broze Jr GJ. Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency. Blood 2008; 111 (10) 4973-4978
- 6 Al-Shanqeeti A, van Hylckama Vlieg A, Berntorp E, Rosendaal FR, Broze Jr GJ. Protein Z and protein Z-dependent protease inhibitor. Determinants of levels and risk of venous thrombosis. Thromb Haemost 2005; 93 (03) 411-413
- 7 Corral J, González-Conejero R, Hernández-Espinosa D, Vicente V. Protein Z/Z-dependent protease inhibitor (PZ/ZPI) anticoagulant system and thrombosis. Br J Haematol 2007; 137 (02) 99-108
- 8 Kalsheker N, Morley S, Morgan K. Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin. Biochem Soc Trans 2002; 30 (02) 93-98
- 9 Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med 2020; 382 (15) 1443-1455
- 10 Janciauskiene S, Larsson S, Larsson P, Virtala R, Jansson L, Stevens T. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun 2004; 321 (03) 592-600
- 11 Paysant J, Soria C, Cornillet-Lefèbvre P. et al. Long-term incubation with IL-4 and IL-10 oppositely modifies procoagulant activity of monocytes and modulates the surface expression of tissue factor and tissue factor pathway inhibitor. Br J Haematol 2005; 131 (03) 356-365
- 12 Adam F, Verbeuren TJ, Fauchère J-L, Guillin M-C, Jandrot-Perrus M. Thrombin-induced platelet PAR4 activation: role of glycoprotein Ib and ADP. J Thromb Haemost 2003; 1 (04) 798-804
- 13 Oelschläger C, Römisch J, Staubitz A. et al. Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. Blood 2002; 99 (11) 4015-4020
- 14 Hayakawa M, Kudo D, Saito S. et al. Antithrombin supplementation and mortality in sepsis-induced disseminated intravascular coagulation: a multicenter retrospective observational ttudy. Shock 2016; 46 (06) 623-631
- 15 White B, Schmidt M, Murphy C. et al. Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 2000; 110 (01) 130-134
- 16 Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D, Cardona AF. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev 2012; 12: CD004388
- 17 Al-Horani RA, Desai UR. Factor XIa inhibitors: a review of the patent literature. Expert Opin Ther Pat 2016; 26: 323-345
- 18 Tucker EI, Verbout NG, Leung PY. et al. Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. Blood 2012; 119 (20) 4762-4768
- 19 Vorlova S, Koch M, Manthey HD. et al. Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice. Thromb Haemost 2017; 117 (01) 176-187
- 20 Tormey CA, Stack G. Use of a cytokine-release assay to demonstrate loss of platelet secretory capacity during blood bank processing and storage. Arch Pathol Lab Med 2014; 138 (11) 1481-1487
- 21 Conlon K, Lloyd A, Chattopadhyay U. et al. CD8+ and CD45RA+ human peripheral blood lymphocytes are potent sources of macrophage inflammatory protein 1 alpha, interleukin-8 and RANTES. Eur J Immunol 1995; 25 (03) 751-756
- 22 Amati AL, Zakrzewicz A, Siebers R. et al. Chemokines (CCL3, CCL4, and CCL5) inhibit ATP-induced release of IL-1β by monocytic cells. Mediators Inflamm 2017; 2017: 1434872
- 23 Butschkau A, Nagel P, Grambow E, Zechner D, Broze Jr GJ, Vollmar B. Contribution of protein Z and protein Z-dependent protease inhibitor in generalized Shwartzman reaction. Crit Care Med 2013; 41 (12) e447-e456