Razanakolona Mahita, Adam Frédéric, Bianchini Elsa, Saller François, Carvalho Allan de, Diehl Jean-Luc, Denis Cécile V, Meziani Ferhat, Borgel Delphine, Helms Julie, Vasse Marc
HITh, INSERM, UMR_S1176, Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France.
Département de réanimation médicale, Hôpital Européen Georges Pompidou, Paris, France.
TH Open. 2021 Jun 25;5(2):e220-e229. doi: 10.1055/s-0041-1730037. eCollection 2021 Apr.
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.
蛋白Z（PZ）依赖性血浆蛋白酶抑制剂（ZPI）是一种糖蛋白，可抑制因子Ⅺa，并在PZ存在的情况下抑制因子Ⅹa。最近，ZPI已被证明是一种急性期蛋白（APP）。由于急性期蛋白通常会下调炎症的有害影响，我们测试了ZPI是否能调节炎症状态下观察到的细胞因子增加。我们观察到，在全血模型中，重组人ZPI（rhZPI）可显著降低脂多糖（LPS）诱导的白细胞介素（IL）-1、IL-6和肿瘤坏死因子-α（TNF-α）水平。这种抑制作用不受PZ或肝素存在的影响。反应环中心的ZPI突变体（Y387A）缺乏抗凝活性，但仍具有抗炎活性。令人惊讶的是，当纯化的单核细胞受到LPS刺激时，rhZPI不会抑制IL-6或TNF-α的合成，而当将淋巴细胞加入单核细胞时则会显示出抑制作用。对淋巴细胞的需求可能是由于CCL5（调节激活正常T细胞表达和分泌的趋化因子）的合成，CCL5是一种主要由活化淋巴细胞产生的趋化因子，由rhZPI诱导产生，并且可以减少全血中促炎细胞因子的产生。最后，我们观察到腹腔注射rhZPI可显著降低小鼠血浆中LPS诱导的IL-6和TNF-α的产生。
