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Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state.
- Source :
-
International immunology [Int Immunol] 2011 Sep; Vol. 23 (9), pp. 537-44. Date of Electronic Publication: 2011 Jul 12. - Publication Year :
- 2011
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Abstract
- Objective: Only little is known about the mechanisms of action of corticosteroids in the treatment of inflammatory liver diseases. As there is increasing evidence that stimulation of the innate immune system plays an important pathogenetic role in these conditions, we hypothesized that steroids may interfere with the activation of the Toll-like receptor (TLR) system of the liver.<br />Methods: To test this hypothesis, murine non-parenchymal liver cells (Kupffer cells, liver sinusoidal endothelial cells) and primary hepatocytes were stimulated with TLR 1-9 ligands in the presence or absence of dexamethasone. Expression of pro- and anti-inflammatory cytokines was determined by quantitative reverse transcription-PCR or ELISA, respectively. Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) activation was assessed by western blot analysis.<br />Results: TLR agonists induced the expression of pro- [tumor necrosis factor-α (TNF-α), IL-6, IL-1β, IFN-β] and anti-inflammatory cytokines [IL-10, transforming growth factor-β (TGF-β)], which was differentially modulated by steroid treatment. TNF-α and IL-6 expression was suppressed by dexamethasone, while IL-10 but not TGF-β was enhanced after TLR stimulation. IFN-β production induced by TLR 4 agonists but not TLR 3 agonists was inhibited by dexamethasone. TLR expression itself was down-regulated by steroid treatment in a cell type-specific manner. These effects were associated with suppression of the TLR-mediated activation of NF-κB.<br />Conclusions: TLR signaling is modulated by corticosteroids in a cell type-specific fashion resulting in down-regulation of TLR expression, suppression of pro-inflammatory and up-regulation of anti-inflammatory cytokines. This represents an as yet unknown mechanism of action for corticosteroids that may at least in part explain their therapeutic effects in inflammatory liver diseases.
- Subjects :
- Animals
Cells, Cultured
Cytokines genetics
Cytokines immunology
Gene Expression Regulation drug effects
Immunity, Innate drug effects
Ligands
Liver immunology
Liver metabolism
Liver pathology
Lymphocyte Activation drug effects
Mice
Mice, Inbred C57BL
NF-kappa B genetics
NF-kappa B metabolism
Signal Transduction drug effects
Signal Transduction immunology
Anti-Inflammatory Agents pharmacology
Cytokines metabolism
Dexamethasone pharmacology
Liver drug effects
Toll-Like Receptors agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2377
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International immunology
- Publication Type :
- Academic Journal
- Accession number :
- 21750146
- Full Text :
- https://doi.org/10.1093/intimm/dxr048