Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide.

Abstract

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.

• Authors: S Furusako, T Takahashi, S Mori, Y Takahashi, T Tsuda, M Namba, H Mochizuki
• Journal: Acta medica Okayama (Acta Med Okayama) Vol. 55 Issue 2 Pg. 105-15 (Apr 2001) ISSN: 0386-300X [Print] Japan
• PMID: 11332197 (Publication Type: Journal Article)

Chemical References

• Lipopolysaccharide Receptors
• Lipopolysaccharides
• Oligonucleotides, Antisense
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Cell Line
• Disease Models, Animal
• Gene Expression
• Genes, Reporter
• Humans
• Lipopolysaccharide Receptors (genetics, metabolism)
• Lipopolysaccharides (therapeutic use)
• Male
• Mice
• Mice, Inbred BALB C
• Oligonucleotides, Antisense (therapeutic use)
• Recombinant Fusion Proteins (metabolism)
• Shock, Septic (chemically induced, drug therapy)
• Survival Rate
• Tumor Necrosis Factor-alpha (metabolism)