The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NFκB and STAT3 pathways in cystic fibrosis cells.
The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NFκB and STAT3 pathways in cystic fibrosis cells.
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DOI：
10.1007/s00011-017-1123-6
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Bifulco M
中科院分区：
文献类型：
--
作者：
Santoro A;Ciaglia E;Nicolin V;Pescatore A;Prota L;Capunzo M;Ursini MV;Nori SL;Bifulco M
N6-异戊烯基腺苷 (iPA) 是甲羟戊酸途径的中间体，具有多种抗癌作用。然而，对其抗炎活性的研究很少，并且潜在的分子机制尚不清楚。因此，我们的目的是研究 iPA 在炎症加剧的人囊性纤维化 (CF) 细胞模型中发挥抗炎作用的能力。 TNFα 刺激的 CF 细胞 CuFi-1 及其正常对应物 NuLi-1 用浓度不断增加的 iPA 进行预处理，并通过 MTT 和 BrdU 测定评估细胞活力和增殖。通过ELISA测定iPA对IL-8和RANTES分泌的影响，并通过Western blot研究信号分子和硒蛋白的激活和表达。为了评估 iPA 对 NFκB 活性的直接影响，对用 NFκB 报告质粒转染的 TNFα 刺激的 HEK293/T 细胞进行荧光素酶测定。我们首次证明 iPA 可阻止 TNFα 刺激的 CF 细胞中 IL-8 和 RANTES 的释放，这种作用是通过增加直接 NFκB 抑制剂 IκBα 的表达并降低 STAT3 的水平来介导的。与此一致的是，我们发现 iPA 抑制 HEK/293T 细胞中 TNFα 介导的 NFκB 激活。最后，我们还发现 iPA 仅在 CF 细胞中提高了谷胱甘肽过氧化物酶 1 和硫氧还蛋白还原酶 1 的水平，表明它能够维持这些抗氧化硒蛋白的充分表达。我们的研究结果表明，iPA 可以发挥抗炎活性，尤其是在 CF 等炎症反应过度的情况下。
N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation. TNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFκB activity, luciferase assay was performed on TNFα-stimulated HEK293/T cells transfected with a NFκB reporter plasmid. We demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFα-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFκB inhibitor IκBα and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFα-mediated NFκB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins. Our findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF.
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影响因子：
3.5
作者：
Gautheron, Jeremie;Pescatore, Alessandra;Courtois, Gilles
通讯作者：
Courtois, Gilles
影响因子：
2.8
作者：
Bifulco, Maurizio;Malfitano, Anna Maria;Laezza, Chiara
通讯作者：
Laezza, Chiara
影响因子：
4.8
作者：
Hallows, KR;Fitch, AC;Pilewski, JM
通讯作者：
Pilewski, JM
影响因子：
3.9
作者：
Cianciola, Nicholas L.;Carlin, Cathleen R.;Kelley, Thomas J.
通讯作者：
Kelley, Thomas J.
影响因子：
6.1
作者：
Amodio, Giuseppina;Sasso, Emanuele;Remondelli, Paolo
通讯作者：
Remondelli, Paolo