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Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbalip.2019.158549 Kamila Prymas 1 , Anna Świątkowska 1 , Gabriela Traczyk 1 , Ewelina Ziemlińska 1 , Anna Dziewulska 2 , Anna Ciesielska 1 , Katarzyna Kwiatkowska 1
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbalip.2019.158549 Kamila Prymas 1 , Anna Świątkowska 1 , Gabriela Traczyk 1 , Ewelina Ziemlińska 1 , Anna Dziewulska 2 , Anna Ciesielska 1 , Katarzyna Kwiatkowska 1
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Bacterial lipopolysaccharide (LPS) is recognized by CD14 protein and the Toll-like receptor (TLR)4/MD2 complex localized in the plasma membrane of immune cells. TLR4 triggers two signaling pathways engaging the MyD88 and TRIF adaptor proteins which lead to production of various pro-inflammatory cytokines. These processes are likely to be modulated by sphingomyelin, as the CD14 - TLR4 interaction takes place in plasma membrane rafts enriched in this lipid. To verify this assumption, we analyzed the influence of tricyclodecane-9-yl xanthogenate (D609), which was proven here to be an SMS inhibitor, and silencing of sphingomyelin synthase (SMS) 1 and/or SMS2 on LPS-induced signaling in macrophages. LPS up-regulated the expression and activity of SMS while exposure to D609 or silencing of SMS1 and SMS2 counteracted this action and led (except for SMS2 silencing) to a depletion of sphingomyelin in cells. Concomitantly, the MyD88- and TRIF-dependent signaling pathways of TLR4 were inhibited with the latter being especially sensitive to the reduction of the SMS1 and/or SMS2 activity. The D609 treatment and SMS1 and/or SMS2 depletion all reduced the level of CD14 protein in cells, which likely was an important determinant of the reduction of the LPS-induced pro-inflammatory responses.
中文翻译：
鞘磷脂合酶活性影响脂多糖刺激的细胞中Toll样受体4的TRIF依赖性信号传导。
细菌脂多糖（LPS）被CD14蛋白和位于免疫细胞质膜中的Toll样受体（TLR）4 / MD2复合物识别。TLR4触发两条信号通路，与MyD88和TRIF衔接子蛋白接合，从而导致产生各种促炎性细胞因子。这些过程可能被鞘磷脂调节，因为CD14-TLR4相互作用发生在富含这种脂质的质膜筏中。为了验证此假设，我们分析了三环癸烷-9-基黄原酸酯（D609）（在此已证明是SMS抑制剂）的影响，以及鞘磷脂合成酶（SMS）1和/或SMS2对LPS诱导巨噬细胞信号转导的沉默。 。当暴露于D609或SMS1和SMS2沉默时，LPS上调SMS的表达和活性，从而抵消了这一作用，并导致细胞中鞘磷脂减少（SMS2沉默除外）。同时，TLR4的依赖MyD88和TRIF的信号通路受到抑制，后者对SMS1和/或SMS2活性的降低尤为敏感。D609处理和SMS1和/或SMS2耗竭均降低了细胞中CD14蛋白的水平，这很可能是LPS诱导的促炎反应减少的重要决定因素。
更新日期：2019-10-31
中文翻译：
鞘磷脂合酶活性影响脂多糖刺激的细胞中Toll样受体4的TRIF依赖性信号传导。
细菌脂多糖（LPS）被CD14蛋白和位于免疫细胞质膜中的Toll样受体（TLR）4 / MD2复合物识别。TLR4触发两条信号通路，与MyD88和TRIF衔接子蛋白接合，从而导致产生各种促炎性细胞因子。这些过程可能被鞘磷脂调节，因为CD14-TLR4相互作用发生在富含这种脂质的质膜筏中。为了验证此假设，我们分析了三环癸烷-9-基黄原酸酯（D609）（在此已证明是SMS抑制剂）的影响，以及鞘磷脂合成酶（SMS）1和/或SMS2对LPS诱导巨噬细胞信号转导的沉默。 。当暴露于D609或SMS1和SMS2沉默时，LPS上调SMS的表达和活性，从而抵消了这一作用，并导致细胞中鞘磷脂减少（SMS2沉默除外）。同时，TLR4的依赖MyD88和TRIF的信号通路受到抑制，后者对SMS1和/或SMS2活性的降低尤为敏感。D609处理和SMS1和/或SMS2耗竭均降低了细胞中CD14蛋白的水平，这很可能是LPS诱导的促炎反应减少的重要决定因素。
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