It has been appreciated for a very long time that infections, particularly bacterial infections of the blood leading to severe sepsis, trigger a hypercoaguable state that sometimes leads to overt disseminated intravascular coagulation. We now recognize that endotoxins and other bacterial, fungal, and viral products can activate the toll receptors, leading to the elaboration of inflammatory cytokines (1) that in turn elicit tissue factor expression to trigger the blood clotting process (2). More recently, we have begun to appreciate the critical role played by natural anticoagulants in controlling the processes leading to septic shock (3). Of these natural anticoagulants, the protein C anticoagulant pathway seems to play a particularly important role in dampening the inflammatory response that occurs with endotoxin and bacteremia. It has now become clear that many of the components in the pathway possess multiple activities that contribute to the regulation of a variety of anticoagulant and antiinflammatory functions. The pathway is illustrated in Fig. S1 (available at http://www. jem. org/cgi/content/full/jem. 20021088/DC1). A key feature of the pathway involves protein C activation on the vascular endothelial cell surface leading to the formation of activated protein C (APC). The activation complex is composed of thrombin and protein C bound respectively to the endothelial cell proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR; references 4–6). APC was originally recognized as an anticoagulant that worked by the proteolytic inactivation of factors Va and VIIIa, thereby shutting down thrombin formation (7, 8). In addition to its anticoagulant activity, APC also possesses antiinflammatory properties. APC is known to inhibit the release of inflammatory cytokines such as tumor necrosis factor in experimental animals challenged with endotoxin (9, 10). APC also limits leukocyte adhesion (11) and protects against an endotoxin-induced decrease in blood pressure (12). At least some of these activities are thought to be due to the ability of APC to inhibit nuclear factor B nuclear translocation (13) and reduce nuclear factor B mRNA levels (14). The multifunctional nature of APC probably accounts for its ability to decrease the death rate in experimental animals (12) and patients (15) with severe sepsis. Recently, attention has begun to shift toward understanding new functions of the protein C activation complex. Like APC, EPCR appears to have antiinflammatory activities. EPCR can be shed from the endothelium by an inducible metalloproteinase (16). Soluble EPCR binds to proteinase 3, an elastase-like enzyme, and this complex can bind to the adhesion integrin CD11b/CD18 (17). The EPCR–APC complex also seems to be important in preventing leukocyte infiltration into tissues (18). Furthermore, several of the antiinflammatory activities of APC seem to be mediated through APC binding to EPCR (19). A new potential role for soluble EPCR was suggested by the recent solution of the crystal structure (20). EPCR was shown to be remarkably similar in structure to the MHC class 1/CD1 family of proteins, most of which are involved in inflammatory processes. The CD1 family are known to bind lipid antigens and present them to T cells (21, 22). This process seems to be important in host defense against infection. Like the CD1 family, EPCR binds a lipid, in this case a phospholipid, in the groove used by CD1 family members for lipid antigen presentation, which suggests by extrapolation that EPCR may also have a function in lipid antigen presentation (20).

In this issue, Conway et al.(23) provide evidence for one additional and important antiinflammatory activity …