The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abstract

Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.

A retrospective comparative study of recombinant human thrombomodulin and gabexate mesilate in sepsis-induced disseminated intravascular coagulation patients

“…This result indicates the superiority of rhTM versus GM with respect to DIC resolution, although we could not calculate the DIC scores on day 7 due to the absence of data. Thrombomodulin has been reported to promote anti-inflammatory effects by suppressing the inflammatory responses induced by high-mobility group-B1 protein [16] or lipopolysaccharides [17]. In our study, rhTM was shown to have improved the SOFA scores and CRP levels on day 7.…”

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…The lectin domain of TM can bind HMGB1 and thereby prevent its interaction with RAGE [64]. Thus, binding of HMGB1 by TM might be a mechanism for terminating RAGE-mediated sustained inflammatory responses.…”

Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome

“…The N-terminal domain of TM binds to and inactivates highmobility group box 1 protein, a proinflammatory cytokine that stimulates the production of inflammatory cytokines such as IL-6 and TNF-a through toll-like receptor 4 and receptors for advanced glycation end products. 7 Aberrant production of proinflammatory cytokines is considered to induce endothelial cell damage and may be involved in the pathogenesis of ES. As a result, rTM may alleviate ES through inactivation of these proinflammatory cytokines.…”