Activation of LXRs using the synthetic agonist GW3965 represses the production of pro-inflammatory cytokines by murine mast cells.
Activation of LXRs using the synthetic agonist GW3965 represses the production of pro-inflammatory cytokines by murine mast cells.
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DOI：
10.1016/j.alit.2015.03.001
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
S. Nunomura;Y. Okayama;Kenji Matsumoto;N. Hashimoto;Kaori Endo-Umeda;T. Terui;M. Makishima;C. Ra
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文献类型：
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作者：
S. Nunomura;Y. Okayama;Kenji Matsumoto;N. Hashimoto;Kaori Endo-Umeda;T. Terui;M. Makishima;C. Ra
背景：肝脏X受体（LXR） a或LXRb的激活可负向调节哺乳动物细胞中促炎基因的表达。我们最近报道了25-羟基胆固醇，一种典型的激活lxr的氧甾醇，在参与高亲和力IgE受体（FcεRI）后，抑制小鼠肥大细胞（MCs）中IL-6的产生。这一发现表明小鼠MCs表达功能性LXRs；然而，lxr依赖性抑制mc介导的促炎细胞因子（包括IL-6）产生的机制尚不清楚。因此，我们利用合成的LXR配体GW3965来检测LXRa和LXRb在小鼠骨髓源性MCs （BMMCs）产生促炎细胞因子中的功能。方法：制备野生型（WT）、LXRaÀ/À和LXRa/bÀ/À小鼠BMMCs。各组BMMCs分别用GW3965预处理，然后用igedeg抗原（Ag）或脂多糖（LPS）刺激。然后使用特异性ELISA试剂盒分析细胞因子的产生。结果：GW3965对LXRs的激活显著降低了igeegerag刺激的WT和LXRaÀ/À BMMCs中IL-1a和IL-1b的产生，但不影响IL-6的产生。然而，GW3965处理在LPS刺激下降低了WT和LXRaÀ/À BMMCs中IL-1a、IL-1b和IL-6的产生，而GW3965介导的对细胞因子产生的抑制在LXRa/bÀ/À BMMCs中几乎不存在。结论：这些发现首次表明，GW3965激活LXRs可减弱抗原或lps诱导的小鼠MCs中促炎细胞因子（如IL-1a和IL-1b）的产生，并且LXRb在lxr介导的细胞因子产生的抑制中发挥重要作用。
Background: The activation of liver X receptor (LXR) a or LXRb negatively regulates the expression of proinflammatory genes in mammalian cells. We recently reported that 25-hydroxycholesterol, a representative LXR-activating oxysterol, suppresses IL-6 production in mouse mast cells (MCs) following its engagement of the high-affinity IgE receptor (FcεRI). This finding suggests that murine MCs express functional LXRs; however, the mechanisms underlying the LXR-dependent repression of the MC-mediated production of pro-inflammatory cytokines, including IL-6, are poorly understood. Therefore, we employed the synthetic LXR ligand GW3965 to examine the functions of LXRa and LXRb in the production of pro-inflammatory cytokines by murine bone marrow-derived MCs (BMMCs). Methods: We prepared BMMCs from wild-type (WT), LXRaÀ/À, and LXRa/bÀ/À mice. Each group of BMMCs was pretreated with GW3965 and then stimulated with IgEþantigen (Ag) or lipopolysaccharide (LPS). Cytokine production was then analyzed using specific ELISA kits. Results: The activation of LXRs by GW3965 significantly attenuated the production of IL-1a and IL-1b, but not of IL-6, in the WT and LXRaÀ/À BMMCs stimulated with IgEþAg. However, GW3965 treatment decreased the production of IL-1a, IL-1b, and IL-6 in WT and LXRaÀ/À BMMCs upon stimulation with LPS, while the GW3965-mediated suppression of cytokine production was nearly absent from the LXRa/bÀ/À BMMCs.Conclusions: These findings demonstrate, for the first time, that the activation of LXRs by GW3965 attenuates the antigen-or LPS-induced production of pro-inflammatory cytokines, such as IL-1a and IL-1b, in murine MCs and that LXRb plays an important role in the LXR-mediated repression of cytokine production.