Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production.
Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production.
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DOI：
10.1016/j.cellimm.2021.104457
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发表时间：
2022-01
影响因子：
4.3
通讯作者：
Ryan JJ
中科院分区：
文献类型：
--
作者：
Taruselli MT;Kolawole EM;Qayum AA;Haque TT;Caslin HL;Abebayehu D;Kee SA;Dailey JM;Jackson KG;Burchett JR;Spence AJ;Pondicherry N;Barnstein BO;Gomez G;Straus DB;Ryan JJ
他汀类药物是用于降低胆固醇的HMG-CoA还原酶抑制剂。它们还可以通过抑制小G蛋白的异戊二烯化来抑制炎症反应。与此一致，我们之前发现氟伐他汀抑制ige介导的肥大细胞功能。然而，一些研究发现他汀类药物诱导巨噬细胞和NK细胞的促炎细胞因子。与IgE信号传导相反，我们发现氟伐他汀增加了il -33诱导的肥大细胞产生TNF和IL-6。这种作用需要关键的肥大细胞生长因子，干细胞因子（SCF）。用甲羟戊酸或类异戊二烯治疗il -33激活的肥大细胞可降低氟伐他汀的作用，表明氟伐他汀至少部分通过减少类异戊二烯的产生起作用。氟伐他汀还能增强il -33诱导的NF-κB转录活性，促进体内中性粒细胞腹膜炎，这是一种需要肥大细胞激活的反应。其他他汀类药物测试没有提高IL-33反应性。因此，这项工作支持了一些他汀类药物意想不到的促炎作用的观察结果，并提出了这种作用可能发生的机制。由于他汀类药物是炎症性疾病重新利用的候选药物，我们的工作强调了解这些药物的多效性和可能的意外作用的重要性。
Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.
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