The cytoprotective protein C pathway for APC anti-inflammatory activity. Anti-inflammatory effects of APC include APC's effects on vascular endothelial cells and APC's effects on leukocytes. Inhibition of inflammatory gene expression on endothelial cells by APC is EPCR and PAR-1 dependent (green arrow). APC also down-regulates expression of vascular adhesion molecules (such as ICAM-1, VCAM-1, and E-selectin) on the endothelial surface in the presence of inflammatory mediators (red block), thereby limiting leukocyte adhesion and infiltration. APC reduces proinflammatory mediator release (such as TNFα and IL-1β) from leukocytes (red block). The mechanisms by which APC acts on leukocytes are incompletely resolved and could involve the receptors EPCR and PAR-1, EPCR alone, or others (green arrows).^38-41  The complex of soluble EPCR (sEPCR) and proteinase 3 (PR3) binds to the integrin complex CD11b/CD18 (α_Mβ₂; Mac-1; CR3) on activated neutrophils. Although speculative at present (indicated by the question mark), binding of (A)PC to sEPCR is retained when sEPCR is bound to proteinase 3, suggesting that sEPCR might mediate APC cellular signals and/or activation of protein C on leukocytes.⁴²