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-κB 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-κB 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.

中文翻译：

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麦考酚酸通过激活NLRP3炎性体增强了THP-1细胞中脂多糖诱导的白介素18的释放。

背景：白介素（IL）-18是一种促炎细胞因子，在宿主防御中具有重要功能。已显示IL-18的成熟和分泌受NOD样受体（NLR）家族含吡啶域3（NLRP3）炎性小体的调节。霉酚酸酯（MMF）的活性代谢产物霉酚酸（MPA）与脂多糖（LPS）能够促进IL-18的分泌，但其机制尚不清楚。本研究旨在探讨MPA与LPS协同诱导IL-18释放的机制。方法：用LPS和MPA刺激THP-1细胞，用或不用caspase-1，Ac-YVAD-cmk或KCl抑制剂处理。通过ELISA测量上清液中的IL-18。NF-κBp-p65，pro-IL-18，NLRP3，用Western印迹法测定切割的caspase-1（p20）的表达。结果：我们发现单独的MPA不能诱导IL-18，而MPA可以增强LPS介导的IL-18释放。MPA不会影响NF-κBp-p65或pro-IL-18的细胞内蛋白水平，但会激活NLRP3炎性体。Ac-YVAD-cmk或细胞外K +的增加阻止了caspase-1的激活并减弱了IL-18的释放。结论：总而言之，MPA与LPS协同作用，通过激活NLRP3炎性体并增加pro-IL-18的降解来诱导IL-18的释放，而不是通过提高pro-IL-18的产生来诱导。Ac-YVAD-cmk或细胞外K +的增加阻止了caspase-1的激活并减弱了IL-18的释放。结论：总而言之，MPA与LPS协同作用，通过激活NLRP3炎性体并增加pro-IL-18的降解来诱导IL-18的释放，而不是通过提高pro-IL-18的产生来诱导。Ac-YVAD-cmk或细胞外K +的增加阻止了caspase-1的激活并减弱了IL-18的释放。结论：总而言之，MPA与LPS协同作用，通过激活NLRP3炎性体并增加pro-IL-18的降解来诱导IL-18的释放，而不是通过提高pro-IL-18的产生来诱导。