Antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappaB abrogate fulminant septic shock induced by S-typhimurium in mice

The aim of this study was to characterize the functional relevance of the t ranscription factor NF-kappaB in the pathogenesis of septic shock. BALB/c m ice were infected with two wild-type (WT 1, WT 2) strains of S. typhimurium that induce NF-kappaB or an escape variant that lacks this ability (P21) a t a dose of 1 x 10(9)/animal, respectively. Furthermore, wild-type infected mice were treated with antisense oligonucleotides directed against NF-kapp aB 24 h before and 3 or 6 h after infection, while mismatched oligonucleoti des were used as controls. Subsequently, the clinical course, histological and immunological alterations were monitored. Infection with WT 1 and WT 2 strains led to lethal septic shock within 24-36 h. In contrast, infection w ith the P21 variant was not followed by fulminant septic shock. Treatment w ith specific antisense oligonucleotides against the p65 subunit of NF-kappa B 24 h before infection prevented the development of fulminant, lethal sept ic shock and was associated with a significant increase of survival. After 20 h, markedly depressed serum levels of interferon (IFN)-gamma and interle ukin (IL)-6 but not IL-10 and tumour necrosis factor (TNF)-alpha were obser ved in p65 antisense-treated compared to mismatched-treated animals. These data show that the ability of S. typhimurium to induce lethal septic shock is critically dependent on their capacity to induce NF-kappaB.