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

Allan De Carvalho,Cécile V Denis,Delphine Borgel,Elsa Bianchini,Ferhat Meziani,François Saller,Frédéric Adam,Jean-Luc Diehl,Julie Helms,Mahita Razanakolona,Marc Vasse

doi:10.1055/s-0041-1730037

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.

Highlights

The protein Z-dependent plasma protease inhibitor (ZPI) is a member of the serpin superfamily identified in human plasma that produces rapid inhibition of factors Xa (FXa) and XIa (FXIa).[1]
Results recombinant human ZPI (rhZPI) inhibits the synthesis of IL-1β, IL-6, tumor necrosis factor- α (TNF-α), and macrophage inhibitory protein-1 (MIP-1) but increases the production of the chemokine CCL5 (RANTES, Regulated upon Activation, Normal T cell Expressed and Secreted)
The production of IL-1β, IL-6, TNF-α, and MIP-1 was significantly decreased in the presence of rhZPI, whereas the induction of CCL5 by LPS was enhanced by ZPI (►Fig. 2)

Summary

Introduction

The protein Z-dependent plasma protease inhibitor (ZPI) is a member of the serpin superfamily identified in human plasma that produces rapid inhibition of factors Xa (FXa) and XIa (FXIa).[1]. It is evident that acute-phase reactants play a role in minimizing the harmful effects of inflammation in host tissue. Α-1 antitrypsin (AAT) is an acute-phase protein belonging to the serpin superfamily.[8] The importance in its role is highlighted by the development of emphysema and other inflammatory conditions in individuals with AAT deficiency.[9] It has been suggested that the increase in AAT levels during acute inflammation may be protective to the host through blocking excessive serine proteinase activity, and by regulating the expression of proinflammatory cytokines.[10] this prompted us to analyze whether ZPI, in addition to its coagulation regulatory activity, could have a role in dampening excessive inflammatory response, which would be of particular interest in septic shock patients. Effects of recombinant human ZPI (rhZPI) was tested both in vitro and in vivo; ►Fig. 1 summarizes the different approaches used

Materials and Methods

Results

Discussion