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 com ponent of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediate d 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 proi nflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8, In the presen t study, we found that CD14 antisense oligonucleotide (ODN) can prevent let hal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 e xpression in a mouse macrophage cell line, RAW264.7, and suppressed product ion of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, a nd we evaluated its efficacy. The consensus antisense ODN rescued mice prim ed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-ind uced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS -elicited CD14 expression in the liver, resulting in a decrease in LPS-indu ced TNF-alpha production. These findings suggest that the CD14 antisense OD N is distributed in the liver and efficiently suppresses LPS-induced TNF-al pha production by reducing CD14 expression on Kupffer cells. This CD14 anti sense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.