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

• Staphylococcus aureus infection is, despite adequate antibiotic treatment, a disease characterized by high mortality. The bacterium triggers an exaggerated 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 hosts response to S. aureus by inhibition of nuclear factor kappaB (NF-kappaB) 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-kappaB and/or a double-stranded oligonucleotide (mCoAP-1) with homology to the murine AP-1 binding site of collagenase IV gene (metalloproteinase-9; MMP-9), solely or in combination with antibiotics. In mice systemically treated with antisense ODN to NF-kappaB p65 alone, the bacterial burden in the kidneys was significantly increased (P = 0.04) The same tendency was seen when 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 antisense treated mice. Surprisingly, this p65 antisense therapy approach, which has turned out to be highly efficient in amelioration of aseptic arthritis and colitis, failed to change the clinical course of either septic arthritis or sepsis. We suggest that interaction with transcription factors leads to increased bacterial burden in vivo, abrogating the potential benefits of the anti-inflammatory properties exerted by these compounds.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Animals

Arthritis

Infectious

drug therapy

immunology

Cloxacillin

therapeutic use

Disease Models

Animal

Female

Interleukin-6

biosynthesis

Kidney

microbiology

Male

Mice

NF-kappa B

antagonists & inhibitors

physiology

Oligonucleotides

Antisense

pharmacology

Penicillins

therapeutic use

Protein Subunits

Sepsis

drug therapy

immunology

Staphylococcal Infections

drug therapy

immunology

Staphylococcus aureus

growth & development

Transcription Factor AP-1

antagonists & inhibitors

physiology

Treatment Outcome

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)