Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide.
CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.
Furusako
S
S
Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka 412-8524, Japan.
Takahashi
T
T
Mori
S
S
Takahashi
Y
Y
Tsuda
T
T
Namba
M
M
Mochizuki
H
H
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha