Mechanisms of Dexamethasone-Mediated Inhibition of Toll-Like Receptor Signaling Induced by Neisseria meningitidis and Streptococcus pneumoniae

Department of Infectious Diseases, Skejby Hospital, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark.
Infection and immunity (Impact Factor: 3.73). 02/2008; 76(1):189-97. DOI: 10.1128/IAI.00856-07
Source: PubMed


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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    • "Dexamethasone was used as a standard compound in all assays. It is also known to inhibit proinflammatory cytokine production in THP-1 cells as well as in human PBMCs (Mogensen et al. 2008). In our studies, we used dexamethasone at 1 ␮M concentration as a standard in all subsequent experiments. "
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    • "Ogawa et al. (2005) found no evidence for the glucocorticoid regulation of TLR expression, whereas Rozkova et al., (2006) showed enhanced TLR2 and TLR4 expression accompanied by decreased dendritic cells maturation in patients treated with high levels of glucocorticoids. Dexamethasone reduces inflammatory cytokine production from peripheral blood mononuclear cells infected with Streptococcus pneumoniae or Neisseria meningitidis by inhibiting the activation of the transcription factor nuclear factor κB, but glucocorticoid does not affect the increased mRNA stability induced by bacterial infection (Mogensen et al., 2008). Here, we measured TLR expression in the whole organ over a long course of time. "
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