Mycophenolic acid enhanced lipopolysaccharide-induced interleukin-18 release in THP-1 cells via activation of the NLRP3 inflammasome
Mycophenolic acid enhanced lipopolysaccharide-induced interleukin-18 release in THP-1 cells via activation of the NLRP3 inflammasome
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DOI：
10.1080/08923973.2019.1652913
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发表时间：
2019-08-19
影响因子：
3.3
通讯作者：
Li, Tianwang
中科院分区：
文献类型：
--
作者：
Huan, Xuechan;Huang, Qidang;Li, Tianwang
背景：白细胞介素（IL）-18是一种促炎细胞因子，在宿主防御中具有重要功能。IL-18的成熟和分泌已被证明是由NOD样受体（NLR）家族的含pyrin结构域3（NLRP 3）炎性体调节。霉酚酸酯（Mycophenolate mofetil，MMF）的活性代谢产物霉酚酸（Mycophenolic acid，MPA）与脂多糖（lipopolysaccharide，LPS）联合可促进IL-18的分泌，但其作用机制尚不清楚。本研究旨在探讨MPA与LPS协同诱导IL-18释放的机制。研究方法：用LPS和MPA刺激THP-1细胞，用或不用caspase-1抑制剂Ac-YVAD-cmk或KCl处理THP-1细胞，用ELISA法测定上清液中的IL-18。通过蛋白质印迹法测量NF-κ B p-p65、pro-IL-18、NLRP 3和裂解的caspase-1（p20）的细胞内蛋白水平。结果：MPA单独不能诱导IL-18的释放，而MPA能促进LPS介导的IL-18的释放。MPA不影响NF-κ B B p-p65或pro-IL-18的细胞内蛋白水平，但激活NLRP 3炎性体。Ac-YVAD-cmk或增加细胞外K+可阻断caspase-1的激活并减弱IL-18的释放。结论：总之，MPA与LPS协同诱导IL-18的释放是通过激活NLRP 3炎性体和增加IL-18原的降解，而不是通过增加IL-18原的产生。
Background: Interleukin (IL)-18 is a pro-inflammatory cytokine that has important functions in host defense. The maturation and secretion of IL-18 has been shown to be regulated by the NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome. Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in association with lipopolysaccharide (LPS), is able to promote the secretion of IL-18, but the mechanism remains unknown. This study aims to explore the mechanism by which MPA synergizes with LPS to induced IL-18 release. Methods: THP-1 cells were stimulated with LPS and MPA and treated with or without the inhibitors of caspase-1, Ac-YVAD-cmk or KCl; IL-18 in the supernatants was measured by ELISA. The intracellular protein levels of NF-kappa B p-p65, pro-IL-18, NLRP3, and cleaved caspase-1(p20) were measured by Western blot. Results: We found that MPA alone failed to induce IL-18, whereas MPA enhanced LPS-mediated IL-18 release. MPA did not affect the intracellular protein levels of NF-kappa B p-p65 or pro-IL-18 but activated the NLRP3 inflammasome. Ac-YVAD-cmk or increasing extracellular K+ blocked the activation of caspase-1 and attenuated the release of IL-18. Conclusions: Taken together, MPA synergized with LPS to induce the release of IL-18 via activating the NLRP3 inflammasome and increasing the degradation of pro-IL-18, rather than by enhancing the production of pro-IL-18.