Endothelial anticoagulant thrombomodulin (TM) as a natural anti-inflammatory, ‘HMG1 blocker’, inhibits pro-inflammatory cell activation

Abstract number: P0181

Abeyama^* K., Kawahara† K., Yamaji† K., Maruyama† I.

†Japan ^*Kagoshima University, Japan;

An endothelial C-type lectin, TM acts as natural anticoagulant by converting thrombin from a procoagulant to an anticoagulant enzyme. Recent studies have suggested anti-inflammatory properties of TM. However the anti-inflammatory mechanisms, beyond binding thrombin and promoting formation of activated protein C, remain uncertain. Here we describe a novel anti-inflammatory property of TM, as a ‘HMG1 blocker’. TM showed significant inhibitory activity for pro-inflammatory events (e.g. respiratory burst and NF-kB activation) triggered by HMG1 release in response to the interaction between pro-inflammatory cells and endothelial cells, which were independent of TM's enhancement of protein C activation or carboxypeptidase activity. Additionally, extra cellular domain of TM, but not of other endothelial C-type lectins, could bind to HMG1 protein. These suggest that neutralization of HMG1 activity by TM possibly promote anti-inflammatory activity. Furthermore, local and systemic administrations of TM or small peptides including TM's functional motif responsible for ‘HMG1 blocker’, could inhibit chemically and UV-induced skin inflammation. Thus, blockade of HMG1/RAGE interaction using TM and/or TM-derivative peptides may provide new insights into therapeutic concept for several HMG1-related pathologies such as hyperinflammatory disease, cancer metastasis and atherosclerosis.