Regulation of inflammation by the protein C system.
OBJECTIVE
To review new findings about the function of the protein C system during inflammation and coagulation.


RESULTS
Coagulation proteases and their cofactors modify the outcome of severe inflammation by engaging signaling-competent cell surface receptors. The central effector protease of the protein C pathway, activated protein C, interacts with the endothelial cell protein C receptor, protease-activated receptors, and other receptors to exert multiple effects on hemostasis and immune cell function. Thrombomodulin controls the complement arm of the innate immune system in a thrombin-dependent manner through activation of the thrombin activatable inhibitor of fibrinolysis, and in a thrombin-independent, constitutive manner via its lectin-like extracellular domain; and inhibits the inflammatory effects of high-mobility box group 1 protein. Protein S not only suppresses coagulation as an enhancing cofactor for the coagulation inhibitors activated protein C and tissue factor pathway inhibitor but also is also a physiologic ligand for the Tyro/axl/Mer-family of receptor tyrosine kinases that mediate an anti-inflammatory regulatory loop of dendritic cell and monocyte inflammatory function.


CONCLUSIONS
The immune-regulatory capacity of the protein C pathway and its individual components emerge as the dominant action of this pathway in the setting of severe inflammation.
Weiler
Hartmut
H
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, USA. Hartmut.Weiler@bcw.edu
D015703:Antigens, CD / Q000502:physiology; D001777:Blood Coagulation / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology; D016638:Critical Illness; D000074283:Endothelial Protein C Receptor; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D007113:Immunity, Innate / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D018180:Thrombomodulin / Q000502:physiology
D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D017293:Protein S; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D003165:Complement System Proteins