An anti-endotoxin peptide that generates from the amino-terminal domain of complement regulatory protein C1 inhibitor.
C1 inhibitor (C1INH), a complement regulatory protein, prevents endotoxin shock via a direct interaction of the amino-terminal domain with gram-negative bacterial lipopolysaccharide (LPS). Importantly, the cleaved, inactive C1INH still is an anti-endotoxin effector indicating the anti-endotoxin peptide that generates from the amino-terminal domain of C1INH. In this study, we first identified that a cleaved fragment within the major part of the amino-terminal domain in in vitro proteolytic analysis of C1INH had an ability to bind to LPS. We synthesized several peptides overlapping the C1INH cleaved fragment. Among these synthetic peptides, a 13-mer derivative peptide at position from 18 to 30, named N2((18-30)), exhibited the most powerful anti-endotoxin activity in vitro, enlightening that it was most strong at binding to LPS, inhibiting the interaction of LPS with LPS-binding protein (LBP), blocking LPS binding to CD14(+) cells, and suppressing production of tumor necrosis factor (TNF)-alpha by murine macrophages, RAW 264.7. In the murine endotoxin shock model, the peptide N2((18-30)) protected mice from LPS-induced lethal septic shock by inhibiting macrophage activation. These data indicate that the peptide N2((18-30)) derived from the amino-terminal region of C1INH is anti-endotoxin.
Zhang
Haimou
H
Center for Infection and Immunity Research, School of Life Sciences, Hubei University, Wuhan, Hubei, PR China.
Li
Jinan
J
Barrington
Robert A
RA
Liang
Gang
G
Qin
Gangjian
G
Liu
Dong-Xu
DX
D000595:Amino Acid Sequence; D000818:Animals; D050718:Complement C1 Inhibitor Protein / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000737:chemistry* / Q000378:metabolism; D007249:Inflammation; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000737:chemistry; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D012769:Shock / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050718:Complement C1 Inhibitor Protein; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha