Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in gram-negative sepsis.
Gram-negative sepsis is a major death cause in intensive care units. Accumulating evidence indicates the protective role of plasma lipoproteins such as high-density lipoprotein (HDL) in sepsis. It has recently been shown that septic HDL is almost depleted from apolipoprotein CI (apoCI), suggesting that apoCI may be a protective factor in sepsis. Sequence analysis revealed that apoCI possesses a highly conserved consensus KVKEKLK binding motif for lipopolysaccharide (LPS), an outer-membrane component of gram-negative bacteria. Through avid binding to LPS involving this motif, apoCI improved the presentation of LPS to macrophages in vitro and in mice, thereby stimulating the inflammatory response to LPS. Moreover, apoCI dose-dependently increased the early inflammatory response to Klebsiella pneumoniae-induced pneumonia, reduced the number of circulating bacteria, and protected mice against fatal sepsis. Our data support the hypothesis that apoCI is a physiological protector against infection by enhancing the early inflammatory response to LPS and suggest that timely increase of apoCI levels could be used to efficiently prevent and treat early sepsis.
Berbée
Jimmy F P
JF
Department of Biomedical Research, TNO-Quality of Life, Leiden, The Netherlands.
van der Hoogt
Caroline C
CC
Kleemann
Robert
R
Schippers
Emile F
EF
Kitchens
Richard L
RL
van Dissel
Jaap T
JT
Bakker-Woudenberg
Irma A J M
IA
Havekes
Louis M
LM
Rensen
Patrick C N
PC
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D001665:Binding Sites; D017124:Conserved Sequence; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D007109:Immunity; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018805:Sepsis / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*
D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D008070:Lipopolysaccharides