Department of Gastroenterology and Hepatology, University Hospital of Essen, Germany.
Int Immunol. 2011 Sep;23(9):537-44. doi: 10.1093/intimm/dxr048. Epub 2011 Jul 12.
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.
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.
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.
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.
人们对皮质甾类药物治疗炎症性肝病的作用机制知之甚少。由于越来越多的证据表明，固有免疫系统的激活在这些疾病中起着重要的致病作用，我们假设皮质甾类药物可能会干扰肝脏 Toll 样受体（TLR）系统的激活。
为了验证这一假设，我们用 TLR1-9 配体刺激鼠非实质肝细胞（枯否细胞、肝窦内皮细胞）和原代肝细胞，同时或不同时用地塞米松处理。通过定量逆转录-PCR 或 ELISA 分别检测前炎症细胞因子和抗炎细胞因子的表达。用 Western blot 分析核因子κB（NF-κB）的激活。
TLR 激动剂诱导前炎症细胞因子（TNF-α、IL-6、IL-1β、IFN-β）和抗炎细胞因子（IL-10、转化生长因子-β[TGF-β]）的表达，而类固醇的处理则对其进行了不同的调节。地塞米松抑制 TNF-α和 IL-6 的表达，而 TLR 刺激后 IL-10 而非 TGF-β的表达增强。地塞米松抑制 TLR4 激动剂而非 TLR3 激动剂诱导的 IFN-β产生。类固醇处理以细胞类型特异性的方式下调 TLR 表达。这些作用与 TLR 介导的 NF-κB 激活的抑制有关。
TLR 信号转导被皮质甾类药物以细胞类型特异性的方式调节，导致 TLR 表达下调、前炎症细胞因子抑制和抗炎细胞因子上调。这代表了皮质甾类药物作用机制的一个未知方面，至少部分解释了它们在炎症性肝病中的治疗效果。
