Regulation of inflammatory responses by activated protein C

Abstract

Activated protein C (APC), a natural anticoagulant, reduces endotoxin (ET)-induced organ failures in experimental animals, such as coagulation abnormalities, pulmonary vascular injury, and hypotension. These therapeutic effects cannot be due to its anticoagulant effects, but are due to inhibition of TNF-α production in vivo. APC inhibits ET-induced increase in TNF-α production in human monocytes by inhibiting activation of both NFκB and AP-1 in vitro. Such an inhibitory effect of APC is dependent on its serine protease activity in vivo and in vitro. Administration of human plasma-derived APC ameliorated coagulation abnormalities without any adverse effects in patients with disseminated intravascular coagulation (DIC). Recombinant APC was reported to reduce the mortality in patients with severe sepsis. These observations strongly suggest that APC plays an important role in regulating inflammation by inhibiting both inflammatory responses and coagulation abnormalities through inhibition of TNF-α production by monocytes.