Regulation mechanism for inflammation mediated by endothelial cell protein C receptor

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The endothelial cell protein C receptor (EPCR) is a type 1 transmembrane protein, which is capable of specific binding of protein C. We established monoclonal antibodies against the molecule, and demonstrated that EPCR was required for protein C activation under the physiological conditions. We also found that the binding function was not restricted to the zymogen form. Activated protein C (APC) bound to EPCR in the same manner as protein C. We detected EPCR expression in cancer cells. Complex formation of APC with EPCR on cancer cells may contribute to progression of cancer via catalytic activity to matrix metaroproteases. We also found the expression of the molecule on keratinocytes and microparticles. They may contribute to regulation of inflammation.It has been demonstrated that APC was useful for therapy of endotoxin shock. Lipopolysaccharide (LPS) is the causative agent, and is known to induce various cell responses mainly mediated by the cell surface complex of Toll-like receptor 4 and MD-2. LPS needs to be processed by LPS-binding protein and CD14 to be recognized by the cell surface receptor complex. To analyze how APC/EPCR complex affects to the LPS-signaling pathway, we prepared recombinant proteins of these molecules. We will try to analyze molecular mechanisms of cross talking between blood coagulation and inflammation.