C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide.
C1 inhibitor (C1INH) is beneficial in animal models of endotoxemia and sepsis. However, the mechanism(s) of C1INH protection remain(s) ill-defined. In this study, we demonstrated that both active C1INH and reactive center-cleaved, inactive C1INH protected mice from lethal Gram-negative endotoxemia. Both forms of C1INH blocked the LPS-binding protein-dependent binding of Salmonella typhimurium LPS to the murine macrophage cell line, RAW 264.7, and suppressed LPS-induced TNF-alpha mRNA expression. Inhibition of LPS binding to RAW 264.7 cells was reversed with anti-C1INH Ab and was more efficient when C1INH was incubated first with LPS rather than with the cells. C1INH also suppressed LPS-induced up-regulation of TNF-alpha mRNA in whole human blood. The interaction of C1INH with LPS was directly demonstrated both by ELISA and by nondenaturing PAGE, but deletion of the amino-terminal 97-aa residues abrogated this binding. Therefore, C1INH, in addition to its function as a serine protease inhibitor, has a novel anti-inflammatory function mediated via its heavily glycosylated amino-terminal non-serpin domain.
Liu
Dongxu
D
Center for Blood Research, Children's Hospital, Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115, USA.
Cai
Shenghe
S
Gu
Xiaogang
X
Scafidi
Jennifer
J
Wu
Xiao
X
Davis
Alvin E
AE
D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D003174:Complement C1 Inactivator Proteins / Q000008:administration & dosage* / Q000378:metabolism*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D005260:Female; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D016019:Survival Analysis
D003174:Complement C1 Inactivator Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments