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. MAIN FINDINGS: 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.