Anti-vascular permeability of the cleaved reactive center loop within the carboxyl-terminal domain of C1 inhibitor

Zhi De Cheng, Meng Yuan Liu, Gao Chen, Hai Mou Zhang, Gang Jian Qin, Gang Liang, Dong Xu Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

C1 inhibitor (C1INH), a member of the serine proteinase inhibitor (serpin) family, functions as an inhibitor of the complement and contact systems. Cleavage of the reactive center loop (RCL) within the carboxyl-terminal domain of C1INH (iC1INH), lacking of serpin function, induces a conformational change in the molecule. Our previous data demonstrated that active, intact C1INH prevents vascular permeability induced by gram-negative bacterial lipopolysaccharide (LPS). In this study, we investigate the role of RCL-cleaved, inactive C1INH (iC1INH) in vascular endothelial activation. In the cultured primary human umbilical vein endothelial cell (HUVEC) monolayer, iC1INH blocked LPS-induced cell injury by evaluated as transendothelial flux, cell detachment, and cytoskeletal disorganization. LPS-induced upregulation of vascular cell adhesion molecule-1 (VCAM-1) could be suppressed by treatment with iC1INH. Studies exploring the underlying mechanism of iC1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-κB activation and nuclear translocation in an IκBα-dependent manner. The inhibitory effect was associated with stabilization of the NF-κB inhibitor IκB and reduction of inhibitor IκB kinase activity. In the model of endotoxin-induced mice, increased plasma leakage in local abdominal skin in response to LPS was reversed by treatment with iC1INH. Furthermore, systemic administration of LPS to mice resulted in increased microvascular permeability in multiple organs, which was reduced by iC1INH. These data provide evidence that iC1INH has an anti-vascular permeability independent on the serpin function.

Original languageEnglish (US)
Pages (from-to)1743-1751
Number of pages9
JournalMolecular Immunology
Volume45
Issue number6
DOIs
StatePublished - Mar 2008

Keywords

  • Adhesion molecule
  • C1 inhibitor
  • Endothelial cell
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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