Abstract
Protein C Inhibitor (PCI) is a secreted serine protease inhibitor, belonging to the family of serpins. In addition to activated protein C PCI inactivates several other proteases of the coagulation and fibrinolytic systems, suggesting a regulatory role in hemostasis. Glycosaminoglycans and certain negatively charged phospholipids, like phosphatidylserine, bind to PCI and modulate its activity. Phosphatidylerine (PS) is exposed on the surface of apoptotic cells and known as a phagocytosis marker. We hypothesized that PCI might bind to PS exposed on apoptotic cells and thereby influence their removal by phagocytosis. Using Jurkat T-lymphocytes and U937 myeloid cells, we show here that PCI binds to apoptotic cells to a similar extent at the same sites as Annexin V, but in a different manner as compared to live cells (defined spots on ∼10–30% of cells). PCI dose dependently decreased phagocytosis of apoptotic Jurkat cells by U937 macrophages. Moreover, the phagocytosis of PS exposing, activated platelets by human blood derived monocytes declined in the presence of PCI. In U937 cells the expression of PCI as well as the surface binding of PCI increased with time of phorbol ester treatment/macrophage differentiation. The results of this study suggest a role of PCI not only for the function and/or maturation of macrophages, but also as a negative regulator of apoptotic cell and activated platelets removal.
Highlights
Protein C Inhibitor (PCI) is a serine protease inhibitor belonging to the class of serpins [1]
In order to investigate a physiological function of this interaction, it was the intention to study the binding characteristics of PCI to cell membranes, as PS and PE are exposed on the surface of apoptotic cells
From previous in vitro data it is known that PCI binding to phospholipids is not dependent on calcium [13], as it is the case for Annexin V [31], frequently used as apoptosis marker
Summary
Protein C Inhibitor (PCI) is a serine protease inhibitor belonging to the class of serpins [1]. PCI has been described as an inhibitor of the vitamin K dependent anticoagulant protease activated protein C (APC) [2]. Elevated blood plasma levels of PCI were detected in male survivors of myocardial infarction [5] and high APC-PCI levels are associated with higher early death rates after aortic surgery [6]. Watanabe et al [7] found higher APC-PCI complex levels in patients suffering from disseminated intravascular coagulation, thrombotic thrombocytopenia, acute myocardial infarction, pulmonary embolism, and deep vein thrombosis. Decreased PCI levels were found in disseminated intravascular coagulation and thrombotic thrombocytopenia, showing the importance and the complexity of the APC-PCI balance in coagulation and several thrombotic disorders [7]
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