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 transcription factor NF-kappaB in the pathogenesis of septic shock. BALB/c mice 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) at a dose of 1 x 109/animal, respectively. Furthermore, wild-type infected mice were treated with antisense oligonucleotides directed against NF-kappaB 24 h before and 3 or 6 h after infection, while mismatched oligonucleotides 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 with the P21 variant was not followed by fulminant septic shock. Treatment with specific antisense oligonucleotides against the p65 subunit of NF-kappaB 24 h before infection prevented the development of fulminant, lethal septic shock and was associated with a significant increase of survival. After 20 h, markedly depressed serum levels of interferon (IFN)-gamma and interleukin (IL)-6 but not IL-10 and tumour necrosis factor (TNF)-alpha were observed 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.
Schlaak
J F
JF
Department of Medicine A, Imperial College, School of Medicine, St. Mary's Hospital, London, UK. j.schlaak@ic.ac.uk
Barreiros
A P
AP
Pettersson
S
S
Schirmacher
P
P
Meyer Zum Büschenfelde
K H
KH
Neurath
M F
MF
D000818:Animals; D020137:Base Pair Mismatch; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D014644:Genetic Variation; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D020319:Oligodeoxyribonucleotides, Antisense; D010442:Peptide Chain Initiation, Translational; D012480:Salmonella Infections / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology*; D012772:Shock, Septic / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013873:Thionucleotides; D051996:Transcription Factor RelA
D016207:Cytokines; D005456:Fluorescent Dyes; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; D051996:Transcription Factor RelA; D016650:Fluorescein-5-isothiocyanate