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

AI Article Synopsis

  • Excessive inflammation plays a significant role in the severity of bacterial meningitis, a serious condition even with antibiotic treatment.
  • Early administration of dexamethasone, an anti-inflammatory drug, has been shown to reduce death and complications from bacterial meningitis.
  • The study investigates how dexamethasone inhibits inflammatory responses triggered by major bacteria in meningitis, revealing that its effects are linked to the timing of treatment and specific molecular pathways.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223664PMC
http://dx.doi.org/10.1128/IAI.00856-07DOI Listing

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