Lars Jørgen Østergaard

Mechanisms of dexamethasone-mediated inhibition of Toll-like receptor signaling induced by Neisseria meningitidis and Streptococcus pneumoniae.

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  • The Department of Infectious Diseases
  • Department of Medical Microbiology and Immunology
Excessive inflammation contributes to the pathogenesis of bacterial meningitis, which remains a serious disease despite treatment with antibiotics. Therefore, anti-inflammatory drugs have important therapeutic potential, and clinical trials have revealed that early treatment with dexamethasone significantly reduces mortality and morbidity from bacterial meningitis. Here we investigate the molecular mechanisms behind the inhibitory effect of dexamethasone upon the inflammatory responses evoked by Neisseria meningitidis and Streptococcus pneumoniae, two of the major causes of bacterial meningitis. The inflammatory cytokine response was dependent on Toll-like receptor signaling and was strongly inhibited by dexamethasone. Activation of the NF-kappaB pathway was targeted at several levels, including inhibition of IkappaB phosphorylation and NF-kappaB DNA-binding activity as well as upregulation of IkappaB alpha synthesis. Our data also revealed that the timing of steroid treatment relative to infection was important for achieving strong inhibition, particularly in response to S. pneumoniae. Altogether, we describe important targets of dexamethasone in the inflammatory responses evoked by N. meningitidis and S. pneumoniae, which may contribute to our understanding of the clinical effect and the importance of timing with respect to corticosteroid treatment during bacterial meningitis.
Udgivelsesdato: 2008-Jan
Original languageEnglish
JournalInfection and Immunity
Pages (from-to)189-97
Number of pages8
Publication statusPublished - 2008

    Research areas

  • Adult, Animals, Cells, Cultured, Dexamethasone, Humans, Immunosuppressive Agents, Macrophages, Mice, Neisseria meningitidis, Neutrophils, RNA, Messenger, Signal Transduction, Streptococcus pneumoniae, Toll-Like Receptors

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