Comprehensive regulatory system of PAMPs/DAMPs by TM-PC/EPCR system

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Endothelial thrombomodulin(TM) bounds DAMPs(Damage Associated Molecular Patterns);HMGB1,a representative DAMPs, histones. Moreover TM also bounds PAMPs(Pathogen Associated Molecular Patterns) ;lipopolysaccaride(LPS), a representative PAMPs, onto the lectin-like domain of the molecule and neutralizes their cytopathic activities, including proinflammatory and procoagulant activities. HMGB1 bound to TM, degraded by thrombin/TM complex and generated the N-terminus deleted HMGB1, named as des-HMGB1. Des-HMGB1 bound onto the receptors RAGE and TLR2-2, -4. However the binding affinity was weak compared to intact HMGB1, suggesting des-form of the molecule may configure a negative feedback loop among HMGB1 and its receptors regulating the diverse activities of HMGB1. Based on the findings, assay of des-HMGB1.may provide significant information in such morbid states including Disseminated Intravascular Coagulation(DIC), sepsis, systemic inflammatory response sybdrome(SIRS) and so on. Therefore we tried to establish specific assay method of des-HMGB1. We got specific monoclonal antibodies to react with the des-HMGB1. Using the monoclonal antibody, we established specific enzyme linked immune sorbent assay(ELISA). The ELISA successfully detected des-HMGB1 with 10% contamination of intact form. Des-HMGB1 was increased the serum from DIC, especially treated with recombinant TM. However the increased des-HMGB1 was decreased rapidly suggesting the rapid turn-over of the des-form. Moreover some patients showed no increased in des-HMGB1 even with recombinant TM treatment, suggesting of the presence or non-responder cases. Thus assessment of des-HMGB1 may be expected to provide a novel information in the DIC, SIRS, sepsis and so on with or without treatment.