Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor
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 modu...
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Georg Thieme Verlag KG
2021-04-01
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doaj-68423b7e0f38437d918b30b1ee14c6aa2021-06-25T22:44:21ZengGeorg Thieme Verlag KGTH Open2512-94652021-04-010502e220e22910.1055/s-0041-1730037Anti-inflammatory Activity of the Protein Z-Dependent Protease InhibitorMahita Razanakolona0Frédéric Adam1Elsa Bianchini2François Saller3Allan de Carvalho4Jean-Luc Diehl5Cécile V. Denis6Ferhat Meziani7Delphine Borgel8Julie Helms9Marc Vasse10HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceDépartement de réanimation médicale, Hôpital Européen Georges Pompidou, Paris, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceFaculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceFaculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, FranceHITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, FranceThe 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.http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1730037protein z-dependent plasma protease inhibitorproinflammatory cytokinesccl5lipopolysaccharidemonocytes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mahita Razanakolona Frédéric Adam Elsa Bianchini François Saller Allan de Carvalho Jean-Luc Diehl Cécile V. Denis Ferhat Meziani Delphine Borgel Julie Helms Marc Vasse |
spellingShingle |
Mahita Razanakolona Frédéric Adam Elsa Bianchini François Saller Allan de Carvalho Jean-Luc Diehl Cécile V. Denis Ferhat Meziani Delphine Borgel Julie Helms Marc Vasse Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor TH Open protein z-dependent plasma protease inhibitor proinflammatory cytokines ccl5 lipopolysaccharide monocytes |
author_facet |
Mahita Razanakolona Frédéric Adam Elsa Bianchini François Saller Allan de Carvalho Jean-Luc Diehl Cécile V. Denis Ferhat Meziani Delphine Borgel Julie Helms Marc Vasse |
author_sort |
Mahita Razanakolona |
title |
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor |
title_short |
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor |
title_full |
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor |
title_fullStr |
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor |
title_full_unstemmed |
Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor |
title_sort |
anti-inflammatory activity of the protein z-dependent protease inhibitor |
publisher |
Georg Thieme Verlag KG |
series |
TH Open |
issn |
2512-9465 |
publishDate |
2021-04-01 |
description |
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. |
topic |
protein z-dependent plasma protease inhibitor proinflammatory cytokines ccl5 lipopolysaccharide monocytes |
url |
http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1730037 |
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