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CC BY 4.0 · TH Open 2021; 05(02): e220-e229
DOI: 10.1055/s-0041-1730037
Original Article

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

Mahita Razanakolona
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
Frédéric Adam
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
Elsa Bianchini 
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
François Saller
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
Allan de Carvalho
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
Jean-Luc Diehl
2   Département de réanimation médicale, Hôpital Européen Georges Pompidou, Paris, France
,
Cécile V. Denis
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
,
Ferhat Meziani
3   Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France
4   INSERM (French National Institute of Health and Medical Research), Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
,
Delphine Borgel
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
5   APHP, Laboratoire d'Hématologie, Hôpital Universitaire Necker-Enfants Malades, Paris, France
,
Julie Helms
3   Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France
6   ImmunoRhumatologie Moléculaire, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
,
Marc Vasse 
1   HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France
7   Service de Biologie Clinique, Hôpital Foch, Suresnes, France
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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 - monocytes

Supplementary Material



Publication 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/)

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