Impact of transcription factors AP-1 and NF-kappa B on the outcome of experimental Staphylococcus aureus arthritis and sepsis

Staphyloccus aureus infection is, despite adequate antibiotic treatment, a disease characterized by high mortality. The bacterium triggers an exaggera ted immune response in the host, which on the one hand acts as an efficient defense, but on the other hand gives rise to tissue damage. In this study we have modulated the host's response to S, aureus by inhibition of nuclear factor KB (NF-KB) and activator protein-1 (AP-1)-triggered release of pro- inflammatory cytokines and tissue-destructive proteins, respectively. Mice were administered with antisense oligonucleotides (ODN) to the p65 subunit of NF-KB and/or a double-stranded oligonucleotide (mCoAP-1) with homology t o the murine AP-1 binding site of collagenase IV gene (metalloproteinase-9; MMP-9), solely or in combination with antibiotics. In mice systemically tr eated with antisense ODN to NF-KB p65 alone, the bacterial burden in the ki dneys was significantly increased (P = 0.04) The same tendency was seen whe n mCoAP-1 was administered either alone or in combination with antibiotics. We also found significantly (P = 0.04) elevated levels of IL-6 in p65 anti sense treated mice. Surprisingly, this p65 antisense therapy approach, whic h has turned out to be highly efficient in amelioration of aseptic arthriti s and colitis, failed to change the clinical course of either septic arthri tis or sepsis. We suggest that interaction with transcription factors leads to increased bacterial burden in vivo, abrogating the potential benefits o f the antiinflammatory properties exerted by these compounds. (C) 2001 Edit ions scientifiques et medicales Elsevier SAS.